https://hemonc.org/w/api.php?action=feedcontributions&user=Samuelrubinstein&feedformat=atomHemOnc.org - A Hematology Oncology Wiki - User contributions [en]2024-03-29T06:00:14ZUser contributionsMediaWiki 1.35.14https://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=52135Light-chain (AL) amyloidosis2021-09-16T16:18:18Z<p>Samuelrubinstein: /* Doxycycline-CyBorD {{#subobject:1dca0c|Regimen=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Melphalan_.26_Prednisone_.28MP.29|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Melphalan_.26_Prednisone_.28MP.29|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
|2010-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Lenalidomide_.26_Dexamethasone_.28Rd.29|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012 (MC0685)]<br />
|2007-2008<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012 (RV-178)]<br />
|2008-2011<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in RV-178, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# '''MC0685:''' Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed] NCT00564889<br />
<!-- no pre-pub disclosed --><br />
# '''RV-178:''' Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed] NCT00981708<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed] NCT01194791<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab and hyaluronidase, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br>D-VCd: '''<u>D</u>'''aratumumab and hyaluronidase, '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Kastritis et al. 2021 (ANDROMEDA)]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior CHR<br>53.3% vs 18.1%<br>(RR 2.9, 95% CI 2.1-4.1)<br />
|-<br />
|}<br />
''Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.'' <br />
====Targeted therapy====<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] as follows:<br />
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15<br />
**Cycle 7 onwards: 1800 mg SC once on day 1<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
#'''ANDROMEDA:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. [https://doi.org/10.1056/nejmoa2028631 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34192431/ PubMed] NCT03201965<br />
<br />
==Doxycycline-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Doxycycline-CyBorD: '''<u>Doxy</u>'''cycline, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Shen et al. 2021]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#91cf61"|Seems not superior (cardiac PFS HR 0.91, 95% CI, 0.54-1.55)<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Doxycycline]] 100 mg PO twice daily <br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
===References===<br />
# Shen KN, Fu WJ, Wu Y, Dong YJ, Huang ZX, Wei YQ, Li CR, Sun CY, Chen Y, Miao HL, Zhang YL, Cao XX, Zhou DB, Li J. Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial. Circulation. 2021 Sep 10. [https://doi.org/10.1161/CIRCULATIONAHA.121.055953 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34503349/ PubMed] NCT03401372<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
|2004-2006<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Lenalidomide_.26_Dexamethasone_.28Rd.29_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006 (MC0484)]<br />
|2004-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Lenalidomide_.26_Dexamethasone_.28Rd.29_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# '''MC0484:''' Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==Melphalan & Dexamethasone {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==Melphalan & Prednisone (MP) {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5541875/ Hegenbart et al. 2017 (LEOMEX)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012 (RV-AMYL-PI-0219)]<br />
|2008-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010 (BRD 07/7-G)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# '''BRD 07/7-G:''' Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed] NCT00621400<br />
# '''RV-AMYL-PI-0219:''' Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed] NCT00679367<br />
# '''LEOMEX:''' Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5541875/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed] NCT00883623<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==Bortezomib & Dexamethasone (VD) {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6821610/ Minnema et al. 2019 (HOVON 104)]<br />
|2012-2016<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed] NCT01083316<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6821610/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed] NTR3220<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40, uncapped cyclophosphamide {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.3/40, capped cyclophosphamide {{#subobject:e18gua|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Kastritis et al. 2021 (ANDROMEDA)]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Dara-CyBorD|Dara-CyBorD]]<br />
| style="background-color:#d73027" |Inferior CHR<br />
|-<br />
|}<br />
''Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.'' <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #3, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
#'''ANDROMEDA:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. [https://doi.org/10.1056/nejmoa2028631 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34192431/ PubMed] NCT03201965<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: this abstract is no longer available online.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Bortezomib_.26_Dexamethasone_.28VD.29|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Bortezomib_.26_Dexamethasone_.28VD.29|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed] NCT01083316<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==Bortezomib & Dexamethasone (VD) {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Lenalidomide & Dexamethasone (Rd) {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
|2010-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed] NCT01194791<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193746/ Lentzsch et al. 2020 (AAAJ7800)]<br />
|2013-2016<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 May 1;38(13):1455-1462. Epub 2020 Feb 21 [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed] NCT01222260<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
|2005-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
|2005-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [https://doi.org/10.1200/jco.2009.23.8220 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed] NCT00298766<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012 (MC0685)]<br />
|2007-2008<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In MC0685, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*MC0685: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012 (RV-178)]<br />
|2008-2011<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# '''MC0685:''' Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed] NCT00564889<br />
# '''RV-178:''' Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed] NCT00981708<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed] NCT00607581<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Cyclophosphamide & Dexamethasone {{#subobject:8uhgn4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1ytzv5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1 {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1182/blood.2019004369 Roussel et al. 2020 (AMYDARA)]<br />
|2016-2018<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
===Regimen variant #3 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193185/ Sanchorawala et al. 2020 (H-35360)]<br />
|2017-2018<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
# '''AMYDARA:''' Roussel M, Merlini G, Chevret S, Arnulf B, Stoppa AM, Perrot A, Palladini G, Karlin L, Royer B, Huart A, Macro M, Morel P, Frenzel L, Touzeau C, Boyle E, Dorvaux V, Le Bras F, Lavergne D, Bridoux F, Jaccard A. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020 Apr 30;135(18):1531-1540. [https://doi.org/10.1182/blood.2019004369 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32108228/ PubMed] NCT02816476<br />
# '''H-35360:''' Sanchorawala V, Sarosiek S, Schulman A, Mistark M, Migre ME, Cruz R, Sloan JM, Brauneis D, Shelton AC. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020 Apr 30;135(18):1541-1547. [https://doi.org/10.1182/blood.2019004436 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193185/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31978210/ PubMed] NCT02841033<br />
<br />
==Dexamethasone monotherapy {{#subobject:8ug86e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1bc2c5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017 (C16007)]<br />
|2012-NR<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# '''C16007:''' Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed] NCT01318902<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017 (C16007)]<br />
|2012-NR<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# '''C16007:''' Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed] NCT01318902<br />
<br />
==Melphalan & Dexamethasone {{#subobject:8ugjbz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1bqyg5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Pomalidomide & Dexamethasone (PD) {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
|2012-2013<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
|2012-2015<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012 (MC0789)]<br />
|2008-2010<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''MC0789:''' Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed] NCT00558896<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed] NCT01570387<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed] NCT01510613<br />
<br />
==Lenalidomide & Dexamethasone (Rd) {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
|2007-2009<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
|2004-2006<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Lenalidomide & Dexamethasone (RD) {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006 (MC0484)]<br />
|2004-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# '''MC0484:''' Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==Thalidomide & Dexamethasone (TD) {{#subobject:8uuyh1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:25jbv5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=52134Light-chain (AL) amyloidosis2021-09-16T16:17:51Z<p>Samuelrubinstein: /* Regimen {{#subobject:e15b5d|Variant=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Melphalan_.26_Prednisone_.28MP.29|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Melphalan_.26_Prednisone_.28MP.29|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
|2010-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Lenalidomide_.26_Dexamethasone_.28Rd.29|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012 (MC0685)]<br />
|2007-2008<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012 (RV-178)]<br />
|2008-2011<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in RV-178, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# '''MC0685:''' Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed] NCT00564889<br />
<!-- no pre-pub disclosed --><br />
# '''RV-178:''' Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed] NCT00981708<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed] NCT01194791<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab and hyaluronidase, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br>D-VCd: '''<u>D</u>'''aratumumab and hyaluronidase, '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Kastritis et al. 2021 (ANDROMEDA)]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior CHR<br>53.3% vs 18.1%<br>(RR 2.9, 95% CI 2.1-4.1)<br />
|-<br />
|}<br />
''Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.'' <br />
====Targeted therapy====<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] as follows:<br />
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15<br />
**Cycle 7 onwards: 1800 mg SC once on day 1<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
#'''ANDROMEDA:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. [https://doi.org/10.1056/nejmoa2028631 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34192431/ PubMed] NCT03201965<br />
<br />
==Doxycycline-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Doxycycline-CyBorD: '''<u>Doxy</u>'''cycline, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Shen et al. 2021]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#ffffbf"|Seems not superior (cardiac PFS HR 0.91, 95% CI, 0.54-1.55)<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Doxycycline]] 100 mg PO twice daily <br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
===References===<br />
# Shen KN, Fu WJ, Wu Y, Dong YJ, Huang ZX, Wei YQ, Li CR, Sun CY, Chen Y, Miao HL, Zhang YL, Cao XX, Zhou DB, Li J. Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial. Circulation. 2021 Sep 10. [https://doi.org/10.1161/CIRCULATIONAHA.121.055953 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34503349/ PubMed] NCT03401372<br />
<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
|2004-2006<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Lenalidomide_.26_Dexamethasone_.28Rd.29_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006 (MC0484)]<br />
|2004-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Lenalidomide_.26_Dexamethasone_.28Rd.29_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# '''MC0484:''' Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==Melphalan & Dexamethasone {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==Melphalan & Prednisone (MP) {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5541875/ Hegenbart et al. 2017 (LEOMEX)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012 (RV-AMYL-PI-0219)]<br />
|2008-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010 (BRD 07/7-G)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# '''BRD 07/7-G:''' Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed] NCT00621400<br />
# '''RV-AMYL-PI-0219:''' Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed] NCT00679367<br />
# '''LEOMEX:''' Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5541875/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed] NCT00883623<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==Bortezomib & Dexamethasone (VD) {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6821610/ Minnema et al. 2019 (HOVON 104)]<br />
|2012-2016<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed] NCT01083316<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6821610/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed] NTR3220<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40, uncapped cyclophosphamide {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.3/40, capped cyclophosphamide {{#subobject:e18gua|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Kastritis et al. 2021 (ANDROMEDA)]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Dara-CyBorD|Dara-CyBorD]]<br />
| style="background-color:#d73027" |Inferior CHR<br />
|-<br />
|}<br />
''Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.'' <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #3, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
#'''ANDROMEDA:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. [https://doi.org/10.1056/nejmoa2028631 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34192431/ PubMed] NCT03201965<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: this abstract is no longer available online.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Bortezomib_.26_Dexamethasone_.28VD.29|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Bortezomib_.26_Dexamethasone_.28VD.29|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed] NCT01083316<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==Bortezomib & Dexamethasone (VD) {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Lenalidomide & Dexamethasone (Rd) {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
|2010-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed] NCT01194791<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193746/ Lentzsch et al. 2020 (AAAJ7800)]<br />
|2013-2016<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 May 1;38(13):1455-1462. Epub 2020 Feb 21 [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed] NCT01222260<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
|2005-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
|2005-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [https://doi.org/10.1200/jco.2009.23.8220 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed] NCT00298766<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012 (MC0685)]<br />
|2007-2008<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In MC0685, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*MC0685: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012 (RV-178)]<br />
|2008-2011<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# '''MC0685:''' Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed] NCT00564889<br />
# '''RV-178:''' Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed] NCT00981708<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed] NCT00607581<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Cyclophosphamide & Dexamethasone {{#subobject:8uhgn4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1ytzv5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1 {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1182/blood.2019004369 Roussel et al. 2020 (AMYDARA)]<br />
|2016-2018<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
===Regimen variant #3 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193185/ Sanchorawala et al. 2020 (H-35360)]<br />
|2017-2018<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
# '''AMYDARA:''' Roussel M, Merlini G, Chevret S, Arnulf B, Stoppa AM, Perrot A, Palladini G, Karlin L, Royer B, Huart A, Macro M, Morel P, Frenzel L, Touzeau C, Boyle E, Dorvaux V, Le Bras F, Lavergne D, Bridoux F, Jaccard A. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020 Apr 30;135(18):1531-1540. [https://doi.org/10.1182/blood.2019004369 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32108228/ PubMed] NCT02816476<br />
# '''H-35360:''' Sanchorawala V, Sarosiek S, Schulman A, Mistark M, Migre ME, Cruz R, Sloan JM, Brauneis D, Shelton AC. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020 Apr 30;135(18):1541-1547. [https://doi.org/10.1182/blood.2019004436 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193185/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31978210/ PubMed] NCT02841033<br />
<br />
==Dexamethasone monotherapy {{#subobject:8ug86e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1bc2c5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017 (C16007)]<br />
|2012-NR<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# '''C16007:''' Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed] NCT01318902<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017 (C16007)]<br />
|2012-NR<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# '''C16007:''' Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed] NCT01318902<br />
<br />
==Melphalan & Dexamethasone {{#subobject:8ugjbz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1bqyg5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Pomalidomide & Dexamethasone (PD) {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
|2012-2013<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
|2012-2015<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012 (MC0789)]<br />
|2008-2010<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''MC0789:''' Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed] NCT00558896<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed] NCT01570387<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed] NCT01510613<br />
<br />
==Lenalidomide & Dexamethasone (Rd) {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
|2007-2009<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
|2004-2006<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Lenalidomide & Dexamethasone (RD) {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006 (MC0484)]<br />
|2004-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# '''MC0484:''' Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==Thalidomide & Dexamethasone (TD) {{#subobject:8uuyh1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:25jbv5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=52133Light-chain (AL) amyloidosis2021-09-16T16:17:27Z<p>Samuelrubinstein: /* Regimen {{#subobject:e15b5d|Variant=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Melphalan_.26_Prednisone_.28MP.29|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Melphalan_.26_Prednisone_.28MP.29|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
|2010-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Lenalidomide_.26_Dexamethasone_.28Rd.29|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012 (MC0685)]<br />
|2007-2008<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012 (RV-178)]<br />
|2008-2011<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in RV-178, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# '''MC0685:''' Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed] NCT00564889<br />
<!-- no pre-pub disclosed --><br />
# '''RV-178:''' Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed] NCT00981708<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed] NCT01194791<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab and hyaluronidase, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br>D-VCd: '''<u>D</u>'''aratumumab and hyaluronidase, '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Kastritis et al. 2021 (ANDROMEDA)]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior CHR<br>53.3% vs 18.1%<br>(RR 2.9, 95% CI 2.1-4.1)<br />
|-<br />
|}<br />
''Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.'' <br />
====Targeted therapy====<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] as follows:<br />
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15<br />
**Cycle 7 onwards: 1800 mg SC once on day 1<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
#'''ANDROMEDA:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. [https://doi.org/10.1056/nejmoa2028631 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34192431/ PubMed] NCT03201965<br />
<br />
==Doxycycline-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Doxycycline-CyBorD: '''<u>Doxy</u>'''cycline, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Shen et al. 2021]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#ffffbf"|No difference in cardiac PFS (HR 0.91, 95% CI, 0.54-1.55)<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Doxycycline]] 100 mg PO twice daily <br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
===References===<br />
# Shen KN, Fu WJ, Wu Y, Dong YJ, Huang ZX, Wei YQ, Li CR, Sun CY, Chen Y, Miao HL, Zhang YL, Cao XX, Zhou DB, Li J. Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial. Circulation. 2021 Sep 10. [https://doi.org/10.1161/CIRCULATIONAHA.121.055953 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34503349/ PubMed] NCT03401372<br />
<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
|2004-2006<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Lenalidomide_.26_Dexamethasone_.28Rd.29_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006 (MC0484)]<br />
|2004-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Lenalidomide_.26_Dexamethasone_.28Rd.29_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# '''MC0484:''' Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==Melphalan & Dexamethasone {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==Melphalan & Prednisone (MP) {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5541875/ Hegenbart et al. 2017 (LEOMEX)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012 (RV-AMYL-PI-0219)]<br />
|2008-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010 (BRD 07/7-G)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# '''BRD 07/7-G:''' Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed] NCT00621400<br />
# '''RV-AMYL-PI-0219:''' Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed] NCT00679367<br />
# '''LEOMEX:''' Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5541875/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed] NCT00883623<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==Bortezomib & Dexamethasone (VD) {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6821610/ Minnema et al. 2019 (HOVON 104)]<br />
|2012-2016<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed] NCT01083316<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6821610/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed] NTR3220<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40, uncapped cyclophosphamide {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.3/40, capped cyclophosphamide {{#subobject:e18gua|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Kastritis et al. 2021 (ANDROMEDA)]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Dara-CyBorD|Dara-CyBorD]]<br />
| style="background-color:#d73027" |Inferior CHR<br />
|-<br />
|}<br />
''Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.'' <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #3, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
#'''ANDROMEDA:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. [https://doi.org/10.1056/nejmoa2028631 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34192431/ PubMed] NCT03201965<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: this abstract is no longer available online.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Bortezomib_.26_Dexamethasone_.28VD.29|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Bortezomib_.26_Dexamethasone_.28VD.29|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed] NCT01083316<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==Bortezomib & Dexamethasone (VD) {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Lenalidomide & Dexamethasone (Rd) {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
|2010-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed] NCT01194791<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193746/ Lentzsch et al. 2020 (AAAJ7800)]<br />
|2013-2016<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 May 1;38(13):1455-1462. Epub 2020 Feb 21 [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed] NCT01222260<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
|2005-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
|2005-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [https://doi.org/10.1200/jco.2009.23.8220 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed] NCT00298766<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012 (MC0685)]<br />
|2007-2008<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In MC0685, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*MC0685: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012 (RV-178)]<br />
|2008-2011<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# '''MC0685:''' Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed] NCT00564889<br />
# '''RV-178:''' Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed] NCT00981708<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed] NCT00607581<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Cyclophosphamide & Dexamethasone {{#subobject:8uhgn4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1ytzv5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1 {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1182/blood.2019004369 Roussel et al. 2020 (AMYDARA)]<br />
|2016-2018<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
===Regimen variant #3 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193185/ Sanchorawala et al. 2020 (H-35360)]<br />
|2017-2018<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
# '''AMYDARA:''' Roussel M, Merlini G, Chevret S, Arnulf B, Stoppa AM, Perrot A, Palladini G, Karlin L, Royer B, Huart A, Macro M, Morel P, Frenzel L, Touzeau C, Boyle E, Dorvaux V, Le Bras F, Lavergne D, Bridoux F, Jaccard A. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020 Apr 30;135(18):1531-1540. [https://doi.org/10.1182/blood.2019004369 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32108228/ PubMed] NCT02816476<br />
# '''H-35360:''' Sanchorawala V, Sarosiek S, Schulman A, Mistark M, Migre ME, Cruz R, Sloan JM, Brauneis D, Shelton AC. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020 Apr 30;135(18):1541-1547. [https://doi.org/10.1182/blood.2019004436 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193185/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31978210/ PubMed] NCT02841033<br />
<br />
==Dexamethasone monotherapy {{#subobject:8ug86e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1bc2c5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017 (C16007)]<br />
|2012-NR<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# '''C16007:''' Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed] NCT01318902<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017 (C16007)]<br />
|2012-NR<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# '''C16007:''' Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed] NCT01318902<br />
<br />
==Melphalan & Dexamethasone {{#subobject:8ugjbz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1bqyg5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Pomalidomide & Dexamethasone (PD) {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
|2012-2013<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
|2012-2015<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012 (MC0789)]<br />
|2008-2010<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''MC0789:''' Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed] NCT00558896<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed] NCT01570387<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed] NCT01510613<br />
<br />
==Lenalidomide & Dexamethasone (Rd) {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
|2007-2009<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
|2004-2006<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Lenalidomide & Dexamethasone (RD) {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006 (MC0484)]<br />
|2004-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# '''MC0484:''' Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==Thalidomide & Dexamethasone (TD) {{#subobject:8uuyh1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:25jbv5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=52132Light-chain (AL) amyloidosis2021-09-16T16:16:42Z<p>Samuelrubinstein: /* First-line therapy (including transplant ineligible) */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Melphalan_.26_Prednisone_.28MP.29|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Melphalan_.26_Prednisone_.28MP.29|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
|2010-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Lenalidomide_.26_Dexamethasone_.28Rd.29|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012 (MC0685)]<br />
|2007-2008<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012 (RV-178)]<br />
|2008-2011<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in RV-178, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# '''MC0685:''' Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed] NCT00564889<br />
<!-- no pre-pub disclosed --><br />
# '''RV-178:''' Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed] NCT00981708<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed] NCT01194791<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab and hyaluronidase, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br>D-VCd: '''<u>D</u>'''aratumumab and hyaluronidase, '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Kastritis et al. 2021 (ANDROMEDA)]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior CHR<br>53.3% vs 18.1%<br>(RR 2.9, 95% CI 2.1-4.1)<br />
|-<br />
|}<br />
''Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.'' <br />
====Targeted therapy====<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] as follows:<br />
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15<br />
**Cycle 7 onwards: 1800 mg SC once on day 1<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
#'''ANDROMEDA:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. [https://doi.org/10.1056/nejmoa2028631 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34192431/ PubMed] NCT03201965<br />
<br />
==Doxycycline-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Doxycycline-CyBorD: '''<u>Doxy</u>'''cycline, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Shen et al. 2021]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|No difference in cardiac PFS (HR 0.91, 95% CI, 0.54-1.55)<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Doxycycline]] 100 mg PO twice daily <br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
===References===<br />
# Shen KN, Fu WJ, Wu Y, Dong YJ, Huang ZX, Wei YQ, Li CR, Sun CY, Chen Y, Miao HL, Zhang YL, Cao XX, Zhou DB, Li J. Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial. Circulation. 2021 Sep 10. [https://doi.org/10.1161/CIRCULATIONAHA.121.055953 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34503349/ PubMed] NCT03401372<br />
<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
|2004-2006<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Lenalidomide_.26_Dexamethasone_.28Rd.29_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006 (MC0484)]<br />
|2004-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Lenalidomide_.26_Dexamethasone_.28Rd.29_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# '''MC0484:''' Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==Melphalan & Dexamethasone {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==Melphalan & Prednisone (MP) {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5541875/ Hegenbart et al. 2017 (LEOMEX)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012 (RV-AMYL-PI-0219)]<br />
|2008-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010 (BRD 07/7-G)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# '''BRD 07/7-G:''' Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed] NCT00621400<br />
# '''RV-AMYL-PI-0219:''' Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed] NCT00679367<br />
# '''LEOMEX:''' Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc5541875/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed] NCT00883623<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==Bortezomib & Dexamethasone (VD) {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6821610/ Minnema et al. 2019 (HOVON 104)]<br />
|2012-2016<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed] NCT01083316<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6821610/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed] NTR3220<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40, uncapped cyclophosphamide {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.3/40, capped cyclophosphamide {{#subobject:e18gua|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1056/nejmoa2028631 Kastritis et al. 2021 (ANDROMEDA)]<br />
|2018-2019<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Dara-CyBorD|Dara-CyBorD]]<br />
| style="background-color:#d73027" |Inferior CHR<br />
|-<br />
|}<br />
''Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.'' <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #3, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
#'''ANDROMEDA:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. [https://doi.org/10.1056/nejmoa2028631 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34192431/ PubMed] NCT03201965<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: this abstract is no longer available online.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Bortezomib_.26_Dexamethasone_.28VD.29|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
|2010-2013<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Bortezomib_.26_Dexamethasone_.28VD.29|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed] NCT01083316<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#Melphalan_.26_Dexamethasone|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#Bortezomib_.26_Dexamethasone_.28VD.29|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#Bortezomib_.26_Dexamethasone_.28VD.29_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==Bortezomib & Dexamethasone (VD) {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Lenalidomide & Dexamethasone (Rd) {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
|2010-2012<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed] NCT01194791<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193746/ Lentzsch et al. 2020 (AAAJ7800)]<br />
|2013-2016<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 May 1;38(13):1455-1462. Epub 2020 Feb 21 [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed] NCT01222260<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
|2005-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
|2005-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [https://doi.org/10.1200/jco.2009.23.8220 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed] NCT00298766<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012 (MC0685)]<br />
|2007-2008<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
|2008-2009<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In MC0685, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*MC0685: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|Years of enrollment<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012 (RV-178)]<br />
|2008-2011<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# '''MC0685:''' Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed] NCT00564889<br />
# '''RV-178:''' Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed] NCT00981708<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed] NCT00607581<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
|2000-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Cyclophosphamide & Dexamethasone {{#subobject:8uhgn4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1ytzv5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1 {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 40%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1182/blood.2019004369 Roussel et al. 2020 (AMYDARA)]<br />
|2016-2018<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
===Regimen variant #3 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193185/ Sanchorawala et al. 2020 (H-35360)]<br />
|2017-2018<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
# '''AMYDARA:''' Roussel M, Merlini G, Chevret S, Arnulf B, Stoppa AM, Perrot A, Palladini G, Karlin L, Royer B, Huart A, Macro M, Morel P, Frenzel L, Touzeau C, Boyle E, Dorvaux V, Le Bras F, Lavergne D, Bridoux F, Jaccard A. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020 Apr 30;135(18):1531-1540. [https://doi.org/10.1182/blood.2019004369 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32108228/ PubMed] NCT02816476<br />
# '''H-35360:''' Sanchorawala V, Sarosiek S, Schulman A, Mistark M, Migre ME, Cruz R, Sloan JM, Brauneis D, Shelton AC. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020 Apr 30;135(18):1541-1547. [https://doi.org/10.1182/blood.2019004436 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7193185/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31978210/ PubMed] NCT02841033<br />
<br />
==Dexamethasone monotherapy {{#subobject:8ug86e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1bc2c5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017 (C16007)]<br />
|2012-NR<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# '''C16007:''' Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed] NCT01318902<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017 (C16007)]<br />
|2012-NR<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# '''C16007:''' Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed] NCT01318902<br />
<br />
==Melphalan & Dexamethasone {{#subobject:8ugjbz|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:1bqyg5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Pomalidomide & Dexamethasone (PD) {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
|2012-2013<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
|2012-2015<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012 (MC0789)]<br />
|2008-2010<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''MC0789:''' Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed] NCT00558896<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed] NCT01570387<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed] NCT01510613<br />
<br />
==Lenalidomide & Dexamethasone (Rd) {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
|2007-2009<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
|2004-2006<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
==Lenalidomide & Dexamethasone (RD) {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 60%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|Years of enrollment<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006 (MC0484)]<br />
|2004-2005<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# '''MC0484:''' Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==Thalidomide & Dexamethasone (TD) {{#subobject:8uuyh1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:25jbv5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/s41375-021-01317-y Dispenzieri et al. 2021 (Tourmaline-AL1)]<br />
|2012-2018<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Ixazomib_.26_Dexamethasone|Ixazomib & Dexamethasone]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of HRR<br />
|-<br />
|}<br />
''Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
'''28-day cycles'''<br />
===References===<br />
#'''Tourmaline-AL1:''' Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. [https://doi.org/10.1038/s41375-021-01317-y link to original article] [https://pubmed.ncbi.nlm.nih.gov/34168284/ PubMed] NCT01659658<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46961Light-chain (AL) amyloidosis2021-01-21T18:13:12Z<p>Samuelrubinstein: /* Chemotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab and hyaluronidase, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br>D-VCd: '''<u>D</u>'''aratumumab and hyaluronidase, '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] as follows:<br />
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15<br />
**Cycle 7 onwards: 1800 mg SC once on day 1<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''Abstract:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract] NCT03201965<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1 {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ashpublications.org/blood/article/135/18/1531/452572/A-prospective-phase-2-trial-of-daratumumab-in Roussel et al. 2020]<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
===Regimen variant #3 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ashpublications.org/blood/article/135/18/1541/440750/Safety-tolerability-and-response-rates-of Sanchorawala et al. 2020]<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
# Roussel M, Merlini G, Chevret S, Arnulf B, Stoppa AM, Perrot A, Palladini G, Karlin L, Royer B, Huart A, Macro M, Morel P, Frenzel L, Touzeau C, Boyle E, Dorvaux V, Le Bras F, Lavergne D, Bridoux F, Jaccard A. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020 Apr 30;135(18):1531-1540. [https://ashpublications.org/blood/article/135/18/1531/452572/A-prospective-phase-2-trial-of-daratumumab-in link to original article] [https://pubmed.ncbi.nlm.nih.gov/32108228/ PubMed]<br />
# Sanchorawala V, Sarosiek S, Schulman A, Mistark M, Migre ME, Cruz R, Sloan JM, Brauneis D, Shelton AC. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020 Apr 30;135(18):1541-1547. [https://ashpublications.org/blood/article/135/18/1541/440750/Safety-tolerability-and-response-rates-of link to original article] [https://pubmed.ncbi.nlm.nih.gov/31978210/ PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46960Light-chain (AL) amyloidosis2021-01-21T18:12:39Z<p>Samuelrubinstein: /* Dara-CyBorD {{#subobject:1dca0c|Regimen=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab and hyaluronidase, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br>D-VCd: '''<u>D</u>'''aratumumab and hyaluronidase, '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] as follows:<br />
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15<br />
**Cycle 7 onwards: 1800 mg SC once on day 1<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''Abstract:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract] NCT03201965<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1 {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ashpublications.org/blood/article/135/18/1531/452572/A-prospective-phase-2-trial-of-daratumumab-in Roussel et al. 2020]<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
===Regimen variant #3 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ashpublications.org/blood/article/135/18/1541/440750/Safety-tolerability-and-response-rates-of Sanchorawala et al. 2020]<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
# Roussel M, Merlini G, Chevret S, Arnulf B, Stoppa AM, Perrot A, Palladini G, Karlin L, Royer B, Huart A, Macro M, Morel P, Frenzel L, Touzeau C, Boyle E, Dorvaux V, Le Bras F, Lavergne D, Bridoux F, Jaccard A. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020 Apr 30;135(18):1531-1540. [https://ashpublications.org/blood/article/135/18/1531/452572/A-prospective-phase-2-trial-of-daratumumab-in link to original article] [https://pubmed.ncbi.nlm.nih.gov/32108228/ PubMed]<br />
# Sanchorawala V, Sarosiek S, Schulman A, Mistark M, Migre ME, Cruz R, Sloan JM, Brauneis D, Shelton AC. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020 Apr 30;135(18):1541-1547. [https://ashpublications.org/blood/article/135/18/1541/440750/Safety-tolerability-and-response-rates-of link to original article] [https://pubmed.ncbi.nlm.nih.gov/31978210/ PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46947Light-chain (AL) amyloidosis2021-01-16T17:13:00Z<p>Samuelrubinstein: /* Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab and hyaluronidase, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br>D-VCd: '''<u>D</u>'''aratumumab and hyaluronidase, '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] as follows:<br />
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15<br />
**Cycle 7 onwards: 1800 mg SC once on day 1<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''Abstract:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract] NCT03201965<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
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M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
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MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
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MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1 {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen variant #2 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ashpublications.org/blood/article/135/18/1531/452572/A-prospective-phase-2-trial-of-daratumumab-in Roussel et al. 2020]<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
===Regimen variant #3 {{#subobject:21e2c5|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ashpublications.org/blood/article/135/18/1541/440750/Safety-tolerability-and-response-rates-of Sanchorawala et al. 2020]<br />
| style="background-color:#91cf61" |Phase II <br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
# Roussel M, Merlini G, Chevret S, Arnulf B, Stoppa AM, Perrot A, Palladini G, Karlin L, Royer B, Huart A, Macro M, Morel P, Frenzel L, Touzeau C, Boyle E, Dorvaux V, Le Bras F, Lavergne D, Bridoux F, Jaccard A. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020 Apr 30;135(18):1531-1540. [https://ashpublications.org/blood/article/135/18/1531/452572/A-prospective-phase-2-trial-of-daratumumab-in link to original article] [https://pubmed.ncbi.nlm.nih.gov/32108228/ PubMed]<br />
# Sanchorawala V, Sarosiek S, Schulman A, Mistark M, Migre ME, Cruz R, Sloan JM, Brauneis D, Shelton AC. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020 Apr 30;135(18):1541-1547. [https://ashpublications.org/blood/article/135/18/1541/440750/Safety-tolerability-and-response-rates-of link to original article] [https://pubmed.ncbi.nlm.nih.gov/31978210/ PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46946Light-chain (AL) amyloidosis2021-01-16T17:00:00Z<p>Samuelrubinstein: /* Targeted therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab and hyaluronidase, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br>D-VCd: '''<u>D</u>'''aratumumab and hyaluronidase, '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab and hyaluronidase (Darzalex Faspro)]] as follows:<br />
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15<br />
**Cycle 7 onwards: 1800 mg SC once on day 1<br />
<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''Abstract:''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract] NCT03201965<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Multiple_myeloma,_induction&diff=46832Multiple myeloma, induction2021-01-02T13:46:14Z<p>Samuelrubinstein: /* KRd {{#subobject:d9be10|Regimen=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
!colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26"|'''Section editor'''<br />
|-<br />
|style="background-color:#F0F0F0"|[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Multiple_myeloma_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''.<br />
<br><big>'''Note: due to its size/complexity, multiple myeloma has been split into sub-pages:'''<br />
*Induction (transplant eligible and ineligible) [''this page'']<br />
*[[Multiple_myeloma,_consolidation_and_maintenance|First-line consolidation and maintenance]]<br />
*[[Multiple_myeloma,_relapsed-refractory|Relapsed/refractory, including subsequent consolidation and maintenance]]<br />
*[[Smoldering multiple myeloma]]<br />
</big><br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
{{#lst:Multiple myeloma|guidelines}}<br />
<section begin=1st-line /><br />
=First-line therapy (including transplant ineligible), randomized data=<br />
''Note: most but not all multiple myeloma first-line regimens specify whether patients are transplant eligible, or not. The top-line inclusion criteria from each prospectively enrolling regimen are reported.''<br />
<br />
==CPR {{#subobject:6ec39f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CPR: '''<u>C</u>'''yclophosphamide, '''<u>P</u>'''rednisone, '''<u>R</u>'''evlimid (Lenalidomide)<br />
<br />
===Regimen {{#subobject:7999a2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]<br />
|rowspan=2|2009-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#MPR|MPR]]<br />
|style="background-color:#fee08b"|Might have inferior PFS<br />
|-<br />
|2. [[#Rd|Rd]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This is the dosing used after a mid-protocol amendment.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day on days 1 to 21<br />
*[[Prednisone (Sterapred)]] 25 mg PO once every other day<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)<br />
<br />
'''28-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide]] versus [[Multiple_myeloma,_consolidation_and_maintenance#RP_2|RP]] maintenance<br />
<br />
===References===<br />
# '''EMN01:''' Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26729895 PubMed]<br />
<br />
==CTD {{#subobject:658a40|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br>CTDa: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone, '''<u>a</u>'''ttenuated<br />
<br />
===Regimen variant #1, CTD {{#subobject:e5fcc6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ Morgan et al. 2010 (MRC Myeloma IX)]<br />
|2003-2007<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|[[#CVAD|CVAD]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''This is an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 100 mg PO once per day <br />
**Cycle 2 onwards, if tolerated: 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*Venous thromboembolism (VTE) prophylaxis was given at physician discretion, but it was suggested that low-risk patients receive [[Aspirin]] and high-risk patients receive [[Warfarin (Coumadin)]] or [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] according to risk categories as described by ''Palumbo A et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–23. [https://doi.org/10.1038/sj.leu.2405062 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18094721 PubMed]''<br />
*Patients in the study were randomized to one of the following until progression:<br />
**[[Clodronate (Bonefos)|Sodium clodronate (Bonefos)]] 1600 mg PO once per day <br />
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 21 to 28 days<br />
<br />
'''21-day cycle for 4 to 6 cycles until maximum response'''<br />
====Subsequent treatment====<br />
*Responding patients: [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan and autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #2, CTDa {{#subobject:db34fc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ Morgan et al. 2010 (MRC Myeloma IX)]<br />
|2003-2007<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Multiple_myeloma_-_historical#MP_.28Prednisolone.29|MP]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''This is a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows, if tolerated:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2: 100 mg PO once per day<br />
**Cycle 3: 150 mg PO once per day<br />
**Cycles 4 to 9: 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*For the first 12 weeks of treatment, thromboprophylaxis was recommended, for example: [[Warfarin (Coumadin)]] or [[:Category:Low molecular weight heparins|low molecular weight heparin]]<br />
*Patients in the study were randomized to a bisphosphonate and received one of the following until progression:<br />
**[[Clodronate (Bonefos)|Sodium clodronate (Bonefos)]] 1600 mg PO once per day <br />
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 21 to 28 days<br />
<br />
'''28-day cycle for 6 to 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Thalidomide_monotherapy|Thalidomide maintenance]] versus [[Multiple_myeloma_-_historical#Observation|no further treatment]]<br />
<br />
===Regimen variant #3 {{#subobject:djfdac|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://link.springer.com/article/10.1007%2Fs00277-015-2537-2 Hungria et al. 2015 (GBRAM0002)]<br />
|rowspan=2|2006-2013<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|1. [[#MPT|MPT]]<br />
| style="background-color:#d9ef8b" |Might have superior ORR<br />
|-<br />
|2. [[#TD|TD]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''Note: the TD arm was close prematurely and no comparisons were made.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 15 to 18<br />
**Cycle 3 onwards: 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
===References===<br />
# '''MRC Myeloma IX:''' Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62051-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131037 PubMed] ISRCTN68454111<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. [http://www.bloodjournal.org/content/118/5/1231.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152492/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21652683 PubMed]<br />
## '''Update:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22021371 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. [http://www.haematologica.org/content/97/3/442.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291601/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22058209 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. [http://clincancerres.aacrjournals.org/content/19/21/6030.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23995858 PubMed]<br />
# '''GBRAM0002:''' Hungria VT, Crusoé EQ, Maiolino A, Bittencourt R, Fantl D, Maciel JF, Pessoa de Magalhaes RJ, Almeida MS, Cury P, Hisgashi F, Peres AL, Chiattone CS. Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible. Ann Hematol. 2016 Jan;95(2):271-8. Epub 2015 Oct 30. [https://link.springer.com/article/10.1007%2Fs00277-015-2537-2 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26518211 PubMed] NCT01532856<br />
<br />
==CVAD {{#subobject:c3a1db|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CVAD: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:51a834|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ Morgan et al. 2010 (MRC Myeloma IX)]<br />
|2003-2007<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#CTD|CTD]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''This is an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Vincristine (Oncovin)]] 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg)<br />
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m<sup>2</sup>)<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*Patients in the study were randomized to a bisphosphonate and received one of the following until progression:<br />
**[[Clodronate (Bonefos)|Sodium clodronate (Bonefos)]] 1600 mg PO once per day <br />
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 21 to 28 days<br />
<br />
'''21-day cycle for 4 to 6 cycles until maximum response'''<br />
====Subsequent treatment====<br />
*Responding patients: [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan and autologous hematopoietic cell transplant]]<br />
<br />
===References===<br />
# '''MRC Myeloma IX:''' Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62051-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131037 PubMed] ISRCTN68454111<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. [http://www.bloodjournal.org/content/118/5/1231.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152492/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21652683 PubMed]<br />
## '''Update:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22021371 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. [http://www.haematologica.org/content/97/3/442.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291601/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22058209 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. [http://clincancerres.aacrjournals.org/content/19/21/6030.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23995858 PubMed]<br />
<br />
==Dara-Rd{{#subobject:5cbbd5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-Rd: '''<u>Dara</u>'''tumumab, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>DRd: '''<u>D</u>'''aratumumab, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable" style="color:white; background-color:#404040"<br />
|<small>'''FDA-recommended dose'''</small><br />
|-<br />
|}<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1817249 Facon et al. 2019 (MAIA)]<br />
|2015-2017<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#Rd|Rd]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older.''<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 7 onwards: 16 mg/kg IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
**For patients with CrCl of 30 to 50 mL/min/1.73m<sup>2</sup> a dose of 10 mg PO once per day on days 1 to 21 was recommended<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**Patients older than 75 years or underweight (BMI less than 18.5) received 20 mg weekly<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''MAIA:''' Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Attal M, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Chiu C, Wang J, Van Rampelbergh R, Uhlar CM, Kobos R, Qi M, Usmani SZ; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-2115. [https://www.nejm.org/doi/full/10.1056/NEJMoa1817249 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31141632 PubMed]<br />
<br />
==Dara-RVd{{#subobject:5coba5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-RVd: '''<u>Dara</u>'''tumumab, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone<br />
<br>D-RVd: '''<u>D</u>'''aratumumab, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:9gaj5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1182/blood.2020005288 Voorhees et al. 2020 (GRIFFIN)]<br />
|2016-2018<br />
|style="background-color:#1a9851"|Randomized Phase II (E-esc)<br />
|[[#RVD|RVd]]<br />
| style="background-color:#d9ef8b" |Might have superior sCR rate<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed multiple myeloma aged 18-70 and eligible for stem cell transplant.''<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] 16 mg/kg IV once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 8, 9, 15, 16<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|Melphalan, then auto HSCT]], then Dara-RVd consolidation<br />
<br />
===References===<br />
#'''GRIFFIN:''' Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, Chari A, Silbermann R, Costa LJ, Anderson LD Jr, Nathwani N, Shah N, Efebera YA, Holstein SA, Costello C, Jakubowiak A, Wildes TM, Orlowski RZ, Shain KH, Cowan AJ, Murphy S, Lutska Y, Pei H, Ukropec J, Vermeulen J, de Boer C, Hoehn D, Lin TS, Richardson PG. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020 Aug 20;136(8):936-945. [https://doi.org/10.1182/blood.2020005288 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32325490 PubMed] NCT02874742<br />
<br />
==Dara-VMP {{#subobject:5cbbd5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-VMP: '''<u>Dara</u>'''tumumab, '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone<br />
<br>D-VMP: '''<u>D</u>'''aratumumab, '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1714678 Mateos et al. 2017 (ALCYONE)]<br />
|2015-2016<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VMP|VMP]]<br />
|style="background-color:#1a9850"|Superior OS (*)<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older. Note that dexamethasone is substituted for prednisone on day 1. Reported efficacy is based on the 2019 update.''<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1: 16 mg/kg IV once per day on days 1, 8, 15, 22, 29, 36<br />
**Cycles 2 to 9: 16 mg/kg IV once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycle 1: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32<br />
**Cycles 2 to 9: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 22, 29<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 2 to 4<br />
<br />
====Supportive medications====<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to each dose of [[Daratumumab (Darzalex)]]<br />
<br />
'''42-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Daratumumab_monotherapy|Daratumumab maintenance]]<br />
===References===<br />
# '''ALCYONE:''' Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1714678 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29231133 PubMed]<br />
## '''Update:''' Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Krevvata M, Chen Y, Wang J, Kudva A, Ukropec J, Wroblewski S, Qi M, Kobos R, San-Miguel J. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2019 Dec 10. [Epub ahead of print] [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32956-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31836199 PubMed]<br />
<br />
==Dara-VTD {{#subobject:5cuc95|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Dara-VTD: '''<u>Dara</u>'''tumumab, '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br>D-VTD: '''<u>D</u>'''aratumumab, '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:e78c2d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31240-1/fulltext Moreau et al. 2019 (CASSIOPEIA)]<br />
|2015-2017<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[#VTD|VTD]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy with stem-cell transplantation.''<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 40 mg PO or IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
**Cycles 3 & 4: 40 mg PO or IV once per day on days 1 & 2, then 20 mg PO or IV once per day on days 8, 9, 15, 16<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|Melphalant with auto HSCT]], then Dara-VTD consolidation<br />
<br />
===References===<br />
# '''CASSIOPEIA:''' Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, Béné MC, Broijl A, Caillon H, Caillot D, Corre J, Delforge M, Dejoie T, Doyen C, Facon T, Sonntag C, Fontan J, Garderet L, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Lenain P, Macro M, Mathiot C, Orsini-Piocelle F, Perrot A, Stoppa AM, van de Donk NW, Wuilleme S, Zweegman S, Kolb B, Touzeau C, Roussel M, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Fermand JP, Escoffre-Barbe M, Eveillard JR, Garidi R, Ahmadi T, Zhuang S, Chiu C, Pei L, de Boer C, Smith E, Deraedt W, Kampfenkel T, Schecter J, Vermeulen J, Avet-Loiseau H, Sonneveld P. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jun 3. [Epub ahead of print] Erratum in: Lancet. 2019 Jun 14. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31240-1/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31171419 PubMed]<br />
<br />
==KMP {{#subobject:95301c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
KMP: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone<br />
<br>CMP: '''<u>C</u>'''arfilzomib, '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:f7a7ed|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/125/20/3100.long Moreau et al. 2015 (CARMYSAP)]<br />
|2010-2012<br />
|style="background-color:#91cf61"|Phase I/II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://www.bloodjournal.org/content/133/18/1953.long Facon et al. 2019 (CLARION)]<br />
|2013-2015<br />
| style="background-color:#1a9851" |Phase III (E-switch-ic)<br />
|[[#VMP|VMP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''CARMYSAP was open to patients older than 65 years of age. Although not explicitly stated, this is considered to be a transplant ineligible population in France. The carfilzomib dose of 36 mg/m<sup>2</sup> was considered to be the MTD in CARMYSAP. CLARION was open to transplant ineligible patients.''<br />
====Targeted therapy====<br />
*[[Carfilzomib (Kyprolis)]] as follows:<br />
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1 & 2, then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 22, 23, 29, 30<br />
**Cycles 2 to 9: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 22, 23, 29, 30<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup>/day PO on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 4<br />
<br />
'''42-day cycle for 9 cycles'''<br />
<br />
===References===<br />
<!-- Philippe Moreau, MD, PhD1*, Brigitte Kolb2*, Cyrille Hulin, MD3*, Denis Caillot, MD4*, Lotfi Benboubker, MD5*, Mourad Tiab, MD6*, Cyrille Touzeau, MD7*, Xavier Leleu, MD8, Murielle Roussel, MD9*, Carine Chaleteix, MD10*, Michel Attal9 and Thierry Facon, MD. Carfilzomib PLUS Melphalan and Prednisone (CMP) Is A Promising Combination Therapy For The Treatment Of Elderly Patients With NEWLY Diagnosed Multiple Myeloma: Results Of A PHASE I/II Trial In 68 CASES. ASH 2013 Abstract 1933. --><br />
# '''CARMYSAP:''' Moreau P, Kolb B, Attal M, Caillot D, Benboubker L, Tiab M, Touzeau C, Leleu X, Roussel M, Chaleteix C, Planche L, Chiffoleau A, Fortin J, Avet-Loiseau H, Mary JY, Hulin C, Facon T. Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood. 2015 May 14;125(20):3100-4. Epub 2015 Mar 17. [http://www.bloodjournal.org/content/125/20/3100.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25784682 PubMed] NCT01279694<br />
# '''CLARION:''' Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos M, Hajek R, Pour L, Jurczyszyn A, Qiu L, Klippel Z, Zahlten-Kumeli A, Osman M, Paiva B, San-Miguel J. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019 May 2;133(18):1953-1963. Epub 2019 Feb 28. [http://www.bloodjournal.org/content/133/18/1953.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/30819926 PubMed]<br />
<br />
==KRd {{#subobject:d9be10|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
KRd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CRd: '''<u>C</u>'''arfilzomib, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:a2dc49|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://oncology.jamanetwork.com/article.aspx?articleid=2363017 Korde et al. 2016 (NCI 11-C-0221)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
''The minimal difference between this and variant #2 below is the steroid dosing.''<br />
====Targeted therapy====<br />
*[[Carfilzomib (Kyprolis)]] as follows:<br />
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1, 2, then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16<br />
**Cycles 2 to 8: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycle 1: 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
**Cycles 2 to 4: 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
**Cycles 5 to 8: 10 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''28-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant. <br />
*If transplant was not undertaken, patients proceeded to [[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|lenalidomide maintenance]] after the 8th cycle<br />
<br />
===Regimen variant #2 {{#subobject:7401c8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ Jakubowiak et al. 2012 (UMCC 2009.056)]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
<br />
''This is the MTD dosing in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Carfilzomib (Kyprolis)]] as follows:<br />
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1, 2, then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16<br />
**Cycles 2 to 8: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 4: 40 mg (route not specified) once per day on days 1, 8, 15, 22<br />
**Cycles 1 & 2 at clinician's discretion: 4 mg IV or PO once per day on days 2, 9, 16 (in addition to above)<br />
**Cycles 5 to 8: 20 mg (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant <br />
*If transplant was not undertaken, patients proceeded to [[Multiple_myeloma,_consolidation_and_maintenance#CRd_.28Carfilzomib.29|CRd maintenance]] after the 8th cycle<br />
<br />
<br />
===Regimen variant #3 {{#subobject:7401c8|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s1470-2045(20)30452-6 Kumar et al. 2020 (ENDURANCE)]<br />
|2013-2019<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#RVD|RVD]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Carfilzomib (Kyprolis)]] as follows:<br />
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1, 2, then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16<br />
**Cycles 2 to 8: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 9 to 12: 10 mg PO once per day on days 1, 2, 8, 9<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide]] x 2 y versus [[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide]] indefinitely<br />
<br />
===References===<br />
# '''UMCC 2009.056:''' Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. [http://www.bloodjournal.org/content/120/9/1801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22665938 PubMed]<br />
<!--<br />
# '''Abstract:''' Korde, Neha; Zingone, Adriana; Kwok, Mary; Manasanch, Elisabet E.; Costello, Rene; Zuchlinski, Diamond; Mulquin, Marcia; Maric, Irina; Calvo, Katherine R; Braylan, Raul C.; Yuan, Constance; Tembhare, Prashant Ramesh; Stetler-Stevenson, Maryalice; Arthur, Diane C; Raffeld, Mark; Xi, Liqiang; Choyke, Peter; Kurdziel, Karen; Lindenberg, Liza; Steinberg, Seth M.; Roschewski, Mark; Landgren, Ola. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients ASH Annual Meeting Abstracts 2012 120: 732 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/732 link to abstract] --><br />
# '''NCI 11-C-0221:''' Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. [http://oncology.jamanetwork.com/article.aspx?articleid=2363017 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26181891 PubMed]<br />
# '''ENDURANCE:''' Kumar SK, Jacobus SJ, Cohen AD, Weiss M, Callander N, Singh AK, Parker TL, Menter A, Yang X, Parsons B, Kumar P, Kapoor P, Rosenberg A, Zonder JA, Faber E Jr, Lonial S, Anderson KC, Richardson PG, Orlowski RZ, Wagner LI, Rajkumar SV. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020 Oct;21(10):1317-1330. Epub 2020 Aug 28. [https://doi.org/10.1016/s1470-2045(20)30452-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/32866432 PubMed] NCT01863550<br />
<br />
==MPR {{#subobject:327863|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MPR: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>R</u>'''evlimid (Lenalidomide)<br />
<br>MPL: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>L</u>'''enalidomide<br />
===Regimen variant #1, 0.13/1.5/10 {{#subobject:926cbb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]<br />
|rowspan=2|2009-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#CPR|CPR]]<br />
|style="background-color:#d9ef8b"|Might have superior PFS<br />
|-<br />
|2. [[#Rd|Rd]]<br />
|style="background-color:#d9ef8b"|Might have superior PFS<br />
|-<br />
|}<br />
''This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant was intended for patients older than 75.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.13 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 1.5 mg/kg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)<br />
<br />
'''28-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide]] versus [[Multiple_myeloma,_consolidation_and_maintenance#RP_2|Lenalidomide & Prednisone maintenance]]<br />
<br />
===Regimen variant #2, 0.18/1.5/10 {{#subobject:a0c09c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]<br />
|rowspan=2|2009-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#CPR|CPR]]<br />
|style="background-color:#d9ef8b"|Might have superior PFS<br />
|-<br />
|2. [[#Rd|Rd]]<br />
|style="background-color:#d9ef8b"|Might have superior PFS<br />
|-<br />
|}<br />
''This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant was intended for patients aged 65 to 75.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 1.5 mg/kg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)<br />
<br />
'''28-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide]] versus [[Multiple_myeloma,_consolidation_and_maintenance#RP_2|Lenalidomide & Prednisone maintenance]]<br />
<br />
===Regimen variant #3, 0.18/2/10 {{#subobject:a4f37a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/28/4459.long Palumbo et al. 2007a]<br />
|2005<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJMoa1112704 Palumbo et al. 2012 (MM-015)]<br />
|rowspan=2|2007-2008<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[Multiple_myeloma_-_historical#MP|MP]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|2. MPR<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|[http://www.bloodjournal.org/content/127/9/1109.long Zweegman et al. 2016 (HOVON87/NMSG18)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#MPT|MPT-T]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''In Palumbo et al. 2007a this regimen was intended for newly diagnosed multiple myeloma patients greater than or equal to 65 years, or younger if ineligible for high-dose therapy. In MM-015 this regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (greater than or equal to 65 years of age). In HOVON87/NMSG18 this regimen was intended for patients greater than 65 years of age or patients less than or equal to 65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*'''HOVON87/NMSG18:'''<br />
**[[Aspirin]] 75 or 80 mg PO once per day or [[Carbasalate calcium (Ascal)]] 100 mg PO once per day<br />
***Patients with a history of VTE received [[:Category:Low molecular weight heparins|LMWH]] instead<br />
**[[:Category:Bisphosphonates|Bisphosphonates]] at physician discretion<br />
**Prophylactic antibiotics at physician discretion<br />
*'''MM-015:''' [[Aspirin]] 75 to 100 mg PO once per day<br />
*'''Palumbo et al. 2007a:''' [[Ciprofloxacin (Cipro)]] 500 mg PO twice per day and [[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===Regimen variant #4, 5/100/10 {{#subobject:eb79d9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ Stewart et al. 2015 (ECOG E1A06)]<br />
|2008-2011<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#MPT|MPT-T]]<br />
|style="background-color:#eeee01"|Seems to have non-inferior PFS<br />
|-<br />
|}<br />
''This regimen was intended for patients who were greater than or equal to 65 years or were less than 65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] was required (dose not specified)<br />
**Full anticoagulation was used for patients at "higher risk" for DVT<br />
*[[Pamidronate (Aredia)]] 90 mg IV once per month recommended for patients with "active bone disease"<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007 Oct 1;25(28):4459-65. Epub 2007 Sep 4. [http://jco.ascopubs.org/content/25/28/4459.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17785703 PubMed]<br />
# '''MM-015:''' Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. [https://www.nejm.org/doi/full/10.1056/NEJMoa1112704 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22571200 PubMed] NCT00405756<br />
# '''ECOG E1A06:''' Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. [http://www.bloodjournal.org/content/126/11/1294.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26157076 PubMed] NCT00602641<br />
# '''EMN01:''' Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26729895 PubMed]<br />
# '''HOVON87/NMSG18:''' Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. [http://www.bloodjournal.org/content/127/9/1109.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26802176 PubMed]<br />
<br />
==MPT {{#subobject:210ba4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MPT: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>T</u>'''halidomide<br />
<br />
===Regimen variant #1, 0.72/8/200 {{#subobject:d23667|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/9/1109.long Zweegman et al. 2016 (HOVON87/NMSG18)]<br />
|2009-2012<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#MPR|MPR-R]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''This regimen was intended for patients greater than 65 years of age or patients less than or equal to 65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day <br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 75 or 80 mg PO once per day or [[Carbasalate calcium (Ascal)]] 100 mg PO once per day<br />
**Patients with a history of VTE received [[:Category:Low molecular weight heparins|LMWH]] instead<br />
*[[:Category:Bisphosphonates|Bisphosphonates]] at physician discretion<br />
*Prophylactic antibiotics at physician discretion<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Thalidomide_monotherapy|Thalidomide maintenance]]<br />
<br />
===Regimen variant #2, 36/400/100 {{#subobject:009af3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ Stewart et al. 2015 (ECOG E1A06)]<br />
|2008-2011<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#MPR|mPR-R]]<br />
|style="background-color:#eeee01"|Seems to have non-inferior PFS<br />
|-<br />
|}<br />
''This regimen was intended for patients who were greater than or equal to 65 years or were less than 65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
<br />
====Supportive medications====<br />
*[[Aspirin]] was required (dose not specified)<br />
**Full anticoagulation was used for patients at "higher risk" for DVT<br />
*[[Pamidronate (Aredia)]] 90 mg IV once per month recommended for patients with "active bone disease"<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Thalidomide_monotherapy|Thalidomide maintenance]]<br />
<br />
===Regimen variant #3 {{#subobject:5b7e29|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJMoa1402551 Benboubker et al. 2014 (FIRST)]<br />
|rowspan=2|2008-2011<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (C)<br />
|1. [[#Rd|Rd]]<br />
|style="background-color:#d73027"|Inferior OS (*)<br />
|-<br />
|2. [[#Rd|Rd18]]<br />
|style="background-color:#fee08b"|Might have inferior OS<br />
|-<br />
|}<br />
''This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Efficacy compared to Rd continuous is based on the 2017 update.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] starting dose as follows:<br />
**Age up to 75 years AND ANC at least 1500/uL AND platelets at least 100 x 10<sup>9</sup>/L: 0.25 mg/kg PO once per day on days 1 to 4<br />
**Older than 75 years AND ANC at least 1500/uL AND platelets at least 100 x 10<sup>9</sup>/L: 0.2 mg/kg PO once per day on days 1 to 4<br />
**Age up to 75 years AND ANC less than 1500/uL but greater than or equal to 1000/uL OR platelets less than 100 x 10<sup>9</sup>/L but greater than or equal to 50 x 10<sup>9</sup>/L: 0.125 mg/kg PO once per day on days 1 to 4<br />
**Older than 75 years AND ANC less than 1500/uL but greater than or equal to 1000/uL OR platelets less than 100 x 10<sup>9</sup>/L but greater than or equal to 50 x 10<sup>9</sup>/L: 0.1 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] starting dose as follows:<br />
**Age up to 75 years: 200 mg PO once per day<br />
**Older than 75 years: 100 mg PO once per day<br />
<br />
'''42-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #4, 36/240/100 {{#subobject:2b9587|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2010.01524.x/abstract Beksac et al. 2010 (TMSG-2005-001)]<br />
|2006-2009<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Multiple_myeloma_-_historical#MP|MP]]<br />
|style="background-color:#91cf60"|Seems to have superior ORR<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
<br />
'''42-day cycle for 9 cycles'''<br />
<br />
===Regimen variant #5, 1/400/400 {{#subobject:6dc18c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/9/1405.long Waage et al. 2010 (NMSG12)]<br />
|2002-2007<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Multiple_myeloma_-_historical#MP|MP]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of OS<br />
|-<br />
|}<br />
''This regimen was intended for patients with previously untreated symptomatic MM, who were not eligible for high-dose treatment with autologous stem cell support.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 100 mg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 200 mg PO once per day for one week, then increased to 400 mg PO once per day<br />
**Cycle 2 onwards: 400 mg PO once per day<br />
<br />
'''42-day cycles until plateau phase'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Thalidomide_monotherapy|Thalidomide maintenance]]<br />
<br />
===Regimen variant #6, 1.25/5/200 {{#subobject:e2f96|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/19/3160.long Wijermans et al. 2010 (HOVON 49)]<br />
|2002-2007<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Multiple_myeloma_-_historical#MP|MP]]<br />
|style="background-color:#d9ef8b"|Might have superior OS<br />
|-<br />
|}<br />
''This regimen was intended for patients with previously untreated MM older than age 65 years.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 5<br />
*[[Prednisone (Sterapred)]] 1 mg/kg PO once per day on days 1 to 5<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day <br />
<br />
====Supportive medications====<br />
*[[:Category:Bisphosphonates|Bisphosphonate]] use recommended with [[Pamidronate (Aredia)]] or [[Clodronate (Bonefos)]]; "a maximum treatment period of 2 years was recommended in patients without active disease."<br />
*During induction therapy, [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] use recommended with [[Nadroparin (Fraxiparine)]] 2,850 units anti-Xa (for patients greater than 90 kg, dose of 5,700 units anti-Xa)<br />
<br />
'''28-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*Thalidomide continues at 200 mg PO once per day for 28 days, then [[Multiple_myeloma,_consolidation_and_maintenance#Thalidomide_monotherapy|thalidomide maintenance]]<br />
<br />
===Regimen variant #7, 0.8/8/100 {{#subobject:1474b2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/22/3664.long Hulin et al. 2009 (IFM 01/01)]<br />
|2002-2006<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Multiple_myeloma_-_historical#MP|MP]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
''This regimen was intended for patients who had stage II or III newly diagnosed multiple myeloma according to the [[#Durie-Salmon_Staging_System_-_1975|Durie-Salmon criteria]] and were at least 75 years of age. Certain stage I patients were allowed; see text for details.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.2 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
<br />
'''42-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #8, 1/8/400 {{#subobject:6de9f0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan="2"|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2807%2961537-2/fulltext Facon et al. 2007 (IFM 99-06)]<br />
|rowspan=2|2000-2005<br />
|rowspan="2" style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[Multiple_myeloma_-_historical#MP|MP]]<br />
|style="background-color:#1a9850"|Superior OS<br />
|-<br />
|2. MEL100<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day, increased as tolerated after 4 weeks on therapy to maximum dose of 400 mg once per day<br />
<br />
'''42-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #9, 28/280/100 {{#subobject:8813e2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2806%2968338-4/fulltext Palumbo et al. 2006 (GISMM2001-A)]<br />
|2002-2005<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Multiple_myeloma_-_historical#MP|MP]]<br />
|style="background-color:#91cf60"|Seems to have superior PFS<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed multiple myeloma aged 60 to 85 years.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 4 mg/m<sup>2</sup> PO once per day on days 1 to 7<br />
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup> PO once per day on days 1 to 7<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day<br />
<br />
====Supportive medications====<br />
*Cycles 1 to 4: [[Enoxaparin (Lovenox)]] 40 mg SC once per day<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Thalidomide_monotherapy|Thalidomide maintenance]]<br />
<br />
===References===<br />
# '''GISMM2001-A:''' Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2806%2968338-4/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16530576 PubMed] NCT00232934<br />
## '''Update:''' Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. [http://www.bloodjournal.org/content/112/8/3107.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18505783 PubMed]<br />
# '''IFM 99-06:''' Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H; Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2807%2961537-2/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17920916 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
<!-- Presented in part in abstract format at the American Society of Clinical Oncology, Chicago, IL, June 1-5, 2007; XIth International Myeloma Workshop, Kos Island, Greece, June 25-30, 2007; and the American Society of Hematology, Atlanta, GA, December 8-11, 2007. --><br />
# '''IFM 01/01:''' Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, Dib M, Guillerm G, Salles B, Eschard JP, Lenain P, Casassus P, Azaïs I, Decaux O, Garderet L, Mathiot C, Fontan J, Lafon I, Virion JM, Moreau P. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009 Aug 1;27(22):3664-70. Epub 2009 May 18. [http://jco.ascopubs.org/content/27/22/3664.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19451428 PubMed]<br />
# '''NMSG12:''' Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. [http://www.bloodjournal.org/content/116/9/1405.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20448107 PubMed]<br />
# '''HOVON 49:''' Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. [http://jco.ascopubs.org/content/28/19/3160.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20516439 PubMed]<br />
# '''TMSG-2005-001:''' Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. [https://onlinelibrary.wiley.com/doi/10.1111/j.1600-0609.2010.01524.x/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20942865 PubMed]<br />
# '''Meta-analysis:''' Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R, Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du Myélome; European Myeloma Network. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011 Aug 4;118(5):1239-47. Epub 2011 Jun 13. [http://www.bloodjournal.org/content/118/5/1239.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/21670471 PubMed]<br />
# '''FIRST:''' Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1402551 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1402551/suppl_file/nejmoa1402551_appendix.pdf link to supplemental appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25184863 PubMed]<br />
## '''Update:''' Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016 Oct;34(30):3609-17. Epub 2016 Jun 20. [http://jco.ascopubs.org/content/34/30/3609.full link to original article] [https://pubmed.ncbi.nlm.nih.gov/27325857 PubMed]<br />
## '''Update:''' Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. Epub 2017 Nov 17. [http://www.bloodjournal.org/content/131/3/301.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/29150421 PubMed]<br />
# '''ECOG E1A06:''' Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. [http://www.bloodjournal.org/content/126/11/1294.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26157076 PubMed] NCT00602641<br />
# '''HOVON87/NMSG18:''' Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. [http://www.bloodjournal.org/content/127/9/1109.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26802176 PubMed]<br />
<br />
==PAD {{#subobject:955a56|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
PAD: '''<u>P</u>'''S-341 (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone<br />
<br>PAd: '''<u>P</u>'''S-341 (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), low-dose '''<u>d</u>'''examethasone<br />
<br>''Note that this regimen is sometimes called VAD but this can create a lot of confusion with the [[Multiple_myeloma_-_historical#VAD|"original" VAD which uses '''<u>V</u>'''incristine]].''<br />
<br>VAD: '''<u>V</u>'''elcade (Bortezomib), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone<br />
<br>BDD: '''<u>B</u>'''ortezomib, '''<u>D</u>'''oxorubicin, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 1/9/40, IV bortezomib {{#subobject:30a4d0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/30/4635.long Ludwig et al. 2010a]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
''Note: This is not specifically a first-line regimen but most patients enrolled on the phase II trial were untreated (50 out of 68). The route of bortezomib was not clearly described in the manuscript but has been confirmed with the authors.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Patients without grade 3 or 4 toxicity during the first two cycles could have bortezomib dose increased to 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 & 4<br />
**Patients without grade 3 or 4 toxicity during the first two cycles could have number of doxorubicin doses increased to 9 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles'''<br />
<br />
===Regimen variant #2, 1.3/9/20, SC bortezomib ("PAd") {{#subobject:60f72e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2015.80 Mai et al. 2015 (GMMG-MM5)]<br />
|2010-2012<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#VDC|VCD]]<br />
|style="background-color:#eeee01"|Non-inferior VGPR or better rate<br />
|-<br />
|}<br />
''This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*[[Trimethoprim-Sulfamethoxazole_(Bactrim_DS)|Cotrimoxazole]] (dose not specified)<br />
*[[Acyclovir (Zovirax)]] (dose not specified)<br />
*[[:Category:Bisphosphonates|Bisphosphonate]] IV every 4 weeks<br />
<br />
'''28-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #3, 1.3/9/40 x 3, IV bortezomib {{#subobject:3fc8cd|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (HOVON-65)]<br />
|2005-2008<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|style="background-color:#1a9850"|Superior PFS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (GMMG-HD4)]<br />
|2005-2008<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|style="background-color:#1a9850"|Superior PFS (*)<br />
|-<br />
|}<br />
''This regimen was intended for patients 18 to 65 years of age with newly diagnosed MM, [[#Durie-Salmon_Staging_System_-_1975|Durie-Salmon stage]] II to III, [[#ECOG_performance_status_.28WHO.2FZubrod_score.29|WHO performance status]] 0 to 2, or WHO 3 when caused by MM. Note that in the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint. Stem cells collected 4 to 6 weeks after induction therapy''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
(described in the appendix of Sonneveld et al. 2012):<br />
*One of the following bisphosphonates recommended:<br />
**[[Pamidronate (Aredia)]] 90 mg IV once every 4 to 6 weeks x at least 2 years<br />
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 4 to 6 weeks x at least 2 years<br />
**[[Ibandronate (Boniva)]] 6 mg IV once every 4 to 6 weeks x at least 2 years<br />
*"Prophylactic antibiotics" (no further specifics) during induction therapy<br />
*Erythropoietin and pain medications at physician discretion<br />
*One of the following for Herpes zoster prophylaxis throughout bortezomib induction:<br />
**[[Acyclovir (Zovirax)]] 800 mg/day PO (did not specify whether taken once per day or as a divided twice per day dose)<br />
**[[Valacyclovir (Valtrex)]] 1000 mg/day PO (did not specify whether taken once per day or as a divided twice per day dose)<br />
<br />
'''28-day cycle for 3 cycles'''<br />
<br />
====Subsequent treatment====<br />
*HOVON-65: [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|Single high-dose melphalan & autologous hematopoietic cell transplant]]<br />
*GMMG-HD4: [[Multiple_myeloma,_consolidation_and_maintenance#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan & autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #4, 1.3/9/40 x 4, IV bortezomib {{#subobject:36a261|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2005.05519.x/full Oakervee et al. 2005]<br />
|style="background-color:#ffffbe"|Phase II, <20 pts (*)<br />
|-<br />
|}<br />
''Note that while this is reported as a phase II, it was also a dose-finding study; only 14 patients were treated at the dose here.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18 <br />
**Cycles 2 to 4: 40 mg PO once per day on days 1 to 4<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Stem_cell_mobilization#Cyclophosphamide_.26_G-CSF|Cyclophosphamide stem cell mobilization]], then [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|high-dose melphalan & autologous hematopoietic cell transplant]]<br />
<br />
===References===<br />
# Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2005.05519.x/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/15953001 PubMed]<br />
<!-- Presented in part at the 13th Congress of the European Haematology Association, June 12-15, 2008, Copenhagen, Denmark; the 50th Annual Meeting of the American Society of Hematology, December 6-9, 2008, San Francisco, CA; and the 51st Annual Meeting of the American Society of Hematology, December 5-8, 2009, New Orleans, LA. --><br />
# Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F, Autzinger EM, Thaler J, Gisslinger H, Lang A, Egyed M, Womastek I, Zojer N. Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin Oncol. 2010 Oct 20;28(30):4635-41. Epub 2010 Sep 7. [http://jco.ascopubs.org/content/28/30/4635.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20823423 PubMed]<br />
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22802322 PubMed]<br />
## '''Subgroup analysis:''' Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. [http://www.bloodjournal.org/content/119/4/940.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/22160383 PubMed]<br />
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://doi.org/10.1038/leu.2017.211 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28761118 PubMed]<br />
# '''GMMG-MM5:''' Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. [https://doi.org/10.1038/leu.2015.80 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25787915 PubMed]<br />
## '''Subgroup analysis:''' Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Weisel K, Duerig J, Goldschmidt H. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015 Jul;100(7):964-9. Epub 2015 Apr 3. [http://www.haematologica.org/content/100/7/964.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486231/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25840597 PubMed]<br />
<br />
==Rd {{#subobject:cf79ea|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, limited duration (4 cycles) {{#subobject:75359c|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042271/ Rajkumar et al. 2009 (ECOG E4A03)]<br />
|2004-2006<br />
|style="background-color:#1a9851"|Phase III (E-de-esc)<br />
|[[Multiple_myeloma_-_historical#RD|RD]]<br />
|style="background-color:#1a9850"|Superior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956597/ Gay et al. 2010]<br />
|2004-2008<br />
|style="background-color:#ffffbe"|Retrospective<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1402888 Palumbo et al. 2014 (MPRvsMEL200)]<br />
|2007-2009<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract Gay et al. 2015 (EMN-441)]<br />
|2009-2011<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|}<br />
''In ECOG E4A03 this is the low-dose dexamethasone arm, and was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h. MPRvsMEL200 was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were 65 years of age or younger. EMN-441 was intended for transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(as described in Rajkumar et al. 2009):<br />
*One of the following bisphosphonates:<br />
**[[Pamidronate (Aredia)]] 90 mg IV over 2 to 4 hours once every 4 weeks<br />
**[[Zoledronic acid (Zometa)]] 4 mg IV over 15 minutes once every 4 weeks<br />
*Thromboprophylaxis mandatory (added mid-protocol after excess rates of DVT)<br />
<br />
'''28-day cycle for 4 cycles (see below)'''<br />
====Subsequent treatment====<br />
*ECOG E4A03: Responding patients could choose after 4 cycles to proceed to [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|high-dose melphalan with autologous hematopoietic cell transplant]] or to continue Rd indefinitely<br />
*ECOG E4A03, non-responders: [[Multiple_myeloma,_relapsed-refractory#TD|Thal-Dex]] (details not described)<br />
*MPRvsMEL200: [[Multiple_myeloma,_consolidation_and_maintenance#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic cell transplant]] versus [[Multiple_myeloma,_consolidation_and_maintenance#MPR_2|MPR consolidation]]<br />
*EMN-441: [[Multiple_myeloma,_consolidation_and_maintenance#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic cell transplant]] versus CRd consolidation<br />
<br />
===Regimen variant #2, limited duration (6 cycles) {{#subobject:6b80b3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext Durie et al. 2016 (SWOG S0777)]<br />
|2008-2012<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#RVD|VRd]]<br />
|style="background-color:#fc8d59"|Seems to have inferior OS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #3, limited duration (9 cycles) {{#subobject:37a149|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]<br />
|rowspan=2|2009-2012<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-de-esc)<br />
|1. [[#CPR|CPR]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#MPR|MPR]]<br />
|style="background-color:#fee08b"|Might have inferior PFS<br />
|-<br />
|}<br />
''This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Age 65 to 75 years: 40 mg PO once per day on days 1, 8, 15, 22<br />
**Age greater than 75 years: 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*One of the following was mandatory:<br />
**[[Aspirin]] or <br />
**[[:Category:Low molecular weight heparins|LMWH]] or <br />
**[[Warfarin (Coumadin)]]<br />
<br />
'''28-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide]] versus [[Multiple_myeloma,_consolidation_and_maintenance#RP_2|RP]] maintenance<br />
<br />
===Regimen variant #4, limited duration (18 cycles, "Rd18") {{#subobject:cad6e3|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJMoa1402551 Benboubker et al. 2014 (FIRST)]<br />
|rowspan=2|2008-2011<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-RT-switch-ooc)<br />
|1. [[#MPT|MPT]]<br />
|style="background-color:#1a9850"|Superior OS (*)<br />
|-<br />
|2. [[#Rd|Rd]]; continuous<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS (*)<br />
|-<br />
|}<br />
''This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Efficacy based on the 2017 update.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] starting dose as follows:<br />
**Normal renal function: 25 mg PO once per day on days 1 to 21<br />
**Moderate renal impairment (CrCl 30 to 50 mL/min/1.73m<sup>2</sup>): 10 mg PO once per day on days 1 to 21<br />
**Severe renal impairment (CrCl less than 30 mL/min/1.73m<sup>2</sup>): 15 mg PO once every other day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] starting dose as follows:<br />
**Age less than or equal to 75: 40 mg PO once per day on days 1, 8, 15, 22<br />
**Age greater than 75: 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 18 cycles'''<br />
<br />
===Regimen variant #5, indefinite 28-day cycles {{#subobject:919b70|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[https://www.nejm.org/doi/full/10.1056/NEJMoa1402551 Benboubker et al. 2014 (FIRST)]<br />
|rowspan=2|2008-2011<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-RT-switch-ooc)<br />
|1. [[#MPT|MPT]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|2. Rd18<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS (*)<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(19)30109-7/fulltext Usmani et al. 2019 (KEYNOTE-185)]<br />
|2016-2017<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Rd & Pembrolizumab<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS (*)<br />
|-<br />
|}<br />
''In FIRST, this regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. Reported efficacy for this arm of FIRST compared to Rd18 is based on the 2017 update. KEYNOTE-185 was closed early due to excess mortality in the experimental arm.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] starting dose as follows:<br />
**Normal renal function: 25 mg PO once per day on days 1 to 21<br />
**Moderate renal impairment (CrCl 30 to 50 mL/min/1.73m<sup>2</sup>): 10 mg PO once per day on days 1 to 21<br />
**Severe renal impairment (CrCl less than 30 mL/min/1.73m<sup>2</sup>): 15 mg PO once every other day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] starting dose as follows:<br />
**Age up to 75 years: 40 mg PO once per day on days 1, 8, 15, 22<br />
**Older than 75 years: 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #6, indefinite with 35-day induction cycles {{#subobject:616f4b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031379/ Zonder et al. 2010 (SWOG S0232)]<br />
|2004-2007<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy|Dexamethasone]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|}<br />
''This regimen was intended for transplantation-ineligible or -denying patients who had to have symptomatic disease with a measurable M-protein, be at least 18 years old, and have a performance status less than 3 (unless resulting from myeloma). Note that the first 3 cycles, termed "induction" in the protocol, were 35-day cycles.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Cycles 1 to 3: 25 mg PO once per day on days 1 to 28<br />
**Cycle 4 onwards: 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
**Cycle 4 onwards: 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day unless already on anticoagulation therapy<br />
<br />
'''35-day cycle for 3 cycles, then 28-day cycles'''<br />
<br />
===Regimen variant #7, indefinite 28-day cycles, first 4 with high-dose dex {{#subobject:cb906d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895238/ Rajkumar et al. 2005]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 <br />
**Cycle 5 onwards: 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 80 mg or 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005 Dec 15;106(13):4050-3. Epub 2005 Aug 23. [http://www.bloodjournal.org/content/106/13/4050.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1895238/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/16118317 PubMed]<br />
# '''ECOG E4A03:''' Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; [[Study_Groups#ECOG|ECOG]]. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21. Erratum in: Lancet Oncol. 2010 Jan;11(1):14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70284-0/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042271/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19853510 PubMed] NCT00098475<br />
## '''Subgroup analysis:''' Jacobus SJ, Kumar S, Uno H, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, Williams ME, Siegel DS, Greipp PR, Rajkumar SV, Fonseca R. Impact of high-risk classification by FISH: an eastern cooperative oncology group (ECOG) study E4A03. Br J Haematol. 2011 Nov;155(3):340-8. Epub 2011 Sep 9. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1365-2141.2011.08849.x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3192237/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21902684 PubMed]<br />
# '''Retrospective:''' Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. [http://dx.doi.org/10.1002/ajh.21777 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956597/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20645430 PubMed]<br />
# '''SWOG S0232:''' Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010 Dec 23;116(26):5838-41. Epub 2010 Sep 27. [http://www.bloodjournal.org/content/116/26/5838.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3031379/ link to PMC article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20876454 PubMed] NCT00064038<br />
# '''MPRvsMEL200:''' Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. [https://www.nejm.org/doi/full/10.1056/NEJMoa1402888 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25184862 PubMed]<br />
# '''FIRST:''' Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa1402551 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1402551/suppl_file/nejmoa1402551_appendix.pdf link to supplemental appendix] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25184863 PubMed]<br />
## '''Update:''' Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016 Oct;34(30):3609-17. Epub 2016 Jun 20. [http://jco.ascopubs.org/content/34/30/3609.full link to original article] [https://pubmed.ncbi.nlm.nih.gov/27325857 PubMed]<br />
## '''Update:''' Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. Epub 2017 Nov 17. [http://www.bloodjournal.org/content/131/3/301.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/29150421 PubMed]<br />
# Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/26596670 PubMed]<br />
# Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26729895 PubMed]<br />
# '''SWOG S0777:''' Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28017406 PubMed]<br />
# '''KEYNOTE-185:''' Usmani SZ, Schjesvold F, Oriol A, Karlin L, Cavo M, Rifkin RM, Yimer HA, LeBlanc R, Takezako N, McCroskey RD, Lim ABM, Suzuki K, Kosugi H, Grigoriadis G, Avivi I, Facon T, Jagannath S, Lonial S, Ghori RU, Farooqui MZH, Marinello P, San-Miguel J; KEYNOTE-185 Investigators. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019 Jul 18. [Epub ahead of print] [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(19)30109-7/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/31327689 PubMed]<br />
<br />
==RVD {{#subobject:97fba9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RVD: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone<br />
<br>VDR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>R</u>'''evlimid (Lenalidomide)<br />
<br>VRd: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
===Synopsis===<br />
Induction therapy prior to autologous stem cell transplantation (ASCT) has evolved dramatically from early days, to its current form of lenalidomide, bortezomib, and dexamethasone (RVD). Both [[Multiple_myeloma,_relapsed-refractory#Rd|lenalidomide]] and [[Multiple_myeloma,_relapsed-refractory#VD|bortezomib]], in combination with dexamethasone, demonstrated promising activity in relapsed/refractory multiple myeloma, before being studied in newly-diagnosed patients.<br><br />
<br>The most relevant studies that have informed clinical practice have demonstrated conclusively that the combination of an immunomodulatory agent (IMiD) and proteasome inhibitor (PI) are most efficacious for disease control and long term outcomes. Intergroup trial SWOG S0777 was a randomized study comparing RVD to Rd for patients with newly diagnosed multiple myeloma, without intention for ASCT ([https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext Durie B et al, Lancet 2017 Feb 4]). This trial showed a median progression-free survival (PFS) of 75 months for the RVD arm, as compared with 64 months for the Rd arm. The IFM 2013-04, next, compared outcomes with an IMiD/PI combination induction (bortezomib, thalidomide, dexamethasone – VTD) with the standard at the time, bortezomib, cyclophosphamide and dexamethasone (VCD) ([http://www.bloodjournal.org/content/127/21/2569.long Moreau P et al Blood 2016 May 26]). Responses to VTD were superior to those for VCD, including rates of CR (19% vs 6%), thus establishing the IMiD and PI combination as the preferred induction regimen. As of 2018, we lack randomized data regarding the addition of daratumumab to RVD vs RVD alone, and also whether carfilzomib, lenalidomide, and dexamethasone (KRd) is superior to RVD, though both of these questions are being examined in ongoing clinical trials.<br><br />
<br>Most variation in this protocol is based on whether it is intended as induction prior to transplant or whether it is part of a transplant-ineligible approach. For the former, 3 cycles are usually given; for the latter, up to 8 cycles are given before transition to maintenance. There is also some variation in how the steroid component is given. To our knowledge, none of the major published trials have used SC bortezomib, although this has been common practice in the clinic since 2010.<br />
===Regimen variant #1, 3 cycles, bi-weekly dexamethasone {{#subobject:45268d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
''This regimen is intended for patients 65 years of age or younger with symptomatic, measurable, newly diagnosed multiple myeloma.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]] versus [[Multiple_myeloma,_consolidation_and_maintenance#RVD|RVD consolidation]]<br />
<br />
===Regimen variant #2, 3 cycles, weekly dexamethasone {{#subobject:fdbb24|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/25/2712.full Roussel et al. 2014 (IFM 2008)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins |Low–molecular weight heparin (LMWH)]]<br />
*[[:Category:Antivirals |Antiviral therapy]] with example [[Valacyclovir (Valtrex) | valacyclovir]] given, for herpes zoster prevention<br />
*[[:Category:Antibacterials |Antibiotic prophylaxis]] with example [[Amoxicillin |amoxicillin]] given, for bacterial infections <br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan and autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #3, 6 cycles, q4wk {{#subobject:ab1b24|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ashpublications.org/blood/article-lookup/doi/10.1182/blood.2019000241 Rosiñol et al. 2019 (PETHEMA/GEM2012)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins |Low–molecular weight heparin (LMWH)]]<br />
*[[:Category:Antivirals |Antiviral therapy]]<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|Melphalan, then auto HSCT]] versus Bu/Mel, then auto HSCT<br />
<br />
===Regimen variant #4, 8 cycles, bi-weekly dexamethasone {{#subobject:81b266|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext Durie et al. 2016 (SWOG S0777)]<br />
|2008-2012<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#Rd|Rd]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
''This regimen is intended for patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Rd|Rd maintenance]]<br />
===Regimen variant #5, 8 cycles, weekly dexamethasone {{#subobject:d90d76|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=3|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]<br />
|rowspan=3|2008-2009<br />
|rowspan=3 style="background-color:#1a9851"|Randomized Phase II (C)<br />
|1. [[#VDC|VDC]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|2. [[#VDC|VDC-mod]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|3. [[#RVDC|VDCR]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|}<br />
''This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a [[#Karnofsky_performance_scale|Karnofsky Performance Status]] greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Bortezomib_monotherapy|Bortezomib consolidation]]<br />
<br />
===Regimen variant #6, 8 cycles, tapered bi-weekly dexamethasone {{#subobject:94d215|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324254/ Richardson et al. 2010]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
''This is the MTD level "4M" described in the manuscript.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg PO once per day <br />
*[[:Category:Antivirals |Antiviral therapy]], such as [[Acyclovir (Zovirax)]] 400 mg PO once per day <br />
*[[:Category:Bisphosphonates|Bisphosphonate]]<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*Patients who responded and tolerated therapy could optionally proceed to [[Multiple_myeloma,_consolidation_and_maintenance#RVD|RVD maintenance]]<br />
<br />
===Regimen variant #7, 12 cycles {{#subobject:94d25t|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1016/s1470-2045(20)30452-6 Kumar et al. 2020 (ENDURANCE)]<br />
|2013-2019<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#KRd|KRd]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 to 8: 1.3 mg/m<sup>2</sup> IV or SC once per day on days 1, 4, 8, 11<br />
**Cycles 9 to 12: 1.3 mg/m<sup>2</sup> IV or SC once per day on days 1 & 8<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 9 to 12: 10 mg PO once per day on days 1, 2, 8, 9<br />
<br />
'''21-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide]] x 2 y versus [[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|Lenalidomide]] indefinitely<br />
===References===<br />
# Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. [http://www.bloodjournal.org/content/116/5/679.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324254/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20385792 PubMed]<br />
<!-- Presented in abstract form at the 51st American Society of Hematology (ASH) annual meeting, New Orleans, LA, December 7, 2009; the 52nd ASH annual meeting, Orlando, FL, December 6, 2010; and the 13th International Myeloma Workshop, Paris, France, May 5, 2011.--><br />
# Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22422823 PubMed]<br />
# '''IFM 2008:''' Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. [http://jco.ascopubs.org/content/32/25/2712.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25024076 PubMed]<br />
# '''SWOG S0777:''' Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28017406 PubMed]<br />
# '''IFM 2009:''' Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28379796 PubMed]<br />
# '''PETHEMA/GEM2012:''' Rosiñol L, Oriol A, Rios R, Sureda A, Blanchard MJ, Hernández MT, Martínez-Martínez R, Moraleda JM, Jarque I, Bargay J, Gironella M, de Arriba F, Palomera L, González-Montes Y, Martí JM, Krsnik I, Arguiñano JM, González ME, González AP, Casado LF, López-Anglada L, Paiva B, Mateos MV, San Miguel JF, Lahuerta JJ, Bladé J. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019 Oct 17;134(16):1337-1345. [https://ashpublications.org/blood/article-lookup/doi/10.1182/blood.2019000241 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/31484647 PubMed]<br />
# '''ENDURANCE:''' Kumar SK, Jacobus SJ, Cohen AD, Weiss M, Callander N, Singh AK, Parker TL, Menter A, Yang X, Parsons B, Kumar P, Kapoor P, Rosenberg A, Zonder JA, Faber E Jr, Lonial S, Anderson KC, Richardson PG, Orlowski RZ, Wagner LI, Rajkumar SV. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020 Oct;21(10):1317-1330. Epub 2020 Aug 28. [https://doi.org/10.1016/s1470-2045(20)30452-6 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32866432 PubMed] NCT01863550<br />
<br />
==RVDC {{#subobject:336f84|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RVDC: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>VDCR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide)<br />
<br />
===Regimen {{#subobject:78af20|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=3|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]<br />
|rowspan=3|2008-2009<br />
|rowspan=3 style="background-color:#1a9851"|Randomized Phase II (E-esc)<br />
|1. [[#VDC|VDC]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|2. [[#VDC|VDC-mod]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|3. [[#RVD|VDR]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|}<br />
''This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a [[#Karnofsky_performance_scale|Karnofsky Performance Status]] greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day <br />
**[[Warfarin (Coumadin)]] or [[Enoxaparin (Lovenox)]] could be used based on physician discretion<br />
*[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended<br />
*[[Acyclovir (Zovirax)]] prophylaxis for Herpes zoster recommended<br />
*[[:Category:Bisphosphonates|Bisphosphonates]] could be used "as necessary"<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Bortezomib_monotherapy|Bortezomib consolidation]]<br />
<br />
===References===<br />
<!-- Presented in abstract form at the 51st American Society of Hematology (ASH) annual meeting, New Orleans, LA, December 7, 2009; the 52nd ASH annual meeting, Orlando, FL, December 6, 2010; and the 13th International Myeloma Workshop, Paris, France, May 5, 2011.--><br />
# '''EVOLUTION:''' Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22422823 PubMed]<br />
<br />
==TAD (Thalidomide) {{#subobject:b583de|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TAD: '''<u>T</u>'''halidomide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:42403f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/115/6/1113 Lokhorst et al. 2009 (HOVON-50)]<br />
|2001-2005<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|[[Complex_multipart_regimens#HOVON-50|See link]]<br />
|style="background-color:#1a9850"|[[Complex_multipart_regimens#HOVON-50|See link]]<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 200 to 400 mg PO once per day<br />
====Chemotherapy====<br />
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup> IV once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
'''28-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Stem_cell_mobilization#CAD_.26_G-CSF|CAD & G-CSF stem-cell mobilization]]<br />
<br />
===References===<br />
<!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008. --><br />
# '''HOVON-50:''' Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19880501 PubMed] ISRCTN06413384<br />
## '''Update:''' van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(18)30149-2/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/30290905 PubMed]<br />
<br />
==TD {{#subobject:13b509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TD: '''<u>T</u>'''halidomide & '''<u>D</u>'''examethasone<br />
<br>Thal-Dex: '''<u>Thal</u>'''idomide & '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 50 -> 200 mg/d, 6 cycles {{#subobject:f79d0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://www.bloodjournal.org/content/120/8/1589.long Rosiñol et al. 2012 (GEM05/MENOS65)]<br />
|rowspan=2|2006-2009<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (C)<br />
|1. [[#VTD|VTD]]<br />
|style="background-color:#fc8d59"|Seems to have inferior PFS<br />
|-<br />
|2. [[Multiple_myeloma_-_historical#VBMCP.2FVBAD|VBMCP/VBAD]], then B<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were less than or equal to 65 years of age with measurable serum and/or urine M protein.''<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28 <br />
**Cycle 2 onwards: [[Thalidomide (Thalomid)]] 200 mg PO once per day on days 1 to 28<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|Low-molecular weight heparin]] or [[Aspirin]] recommended<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 50 -> 200 mg/d, indefinite {{#subobject:d90960|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904367/ Rajkumar et al. 2008 (THAL-MM-003)]<br />
|2003-2005<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy|Dexamethasone]]<br />
|style="background-color:#1a9850"|Superior TTP<br />
|-<br />
|}<br />
''This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.''<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28<br />
**Cycle 2 onwards: 200 mg PO once per day on days 1 to 28<br />
*[[Dexamethasone (Decadron)]] as folows:<br />
**Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 <br />
**Cycle 5 onwards: 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3, 100 -> 200 mg/d, 3 cycles {{#subobject:437335|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61424-9/fulltext Cavo et al. 2010 (GIMEMA MM-BO2005)]<br />
|2006-2008<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#VTD|VTD]]<br />
|style="background-color:#d73027"|Inferior OS (*)<br />
|-<br />
|}<br />
''This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma. Reported efficacy is based on the 2020 update.''<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21 <br />
**Cycles 2 & 3: 200 mg PO once per day on days 1 to 21 <br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem MEL200 with auto HSCT]], with interim Thal-Dex maintenance (see paper for details)<br />
<br />
===Regimen variant #4, 100 -> 200 mg/d, 4 cycles {{#subobject:bc8d0f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/89/7/826.long Cavo et al. 2004 (Bologna 2002)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to end of cycle<br />
**Cycles 2 to 4: 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
**Cycles 2 & 4: 40 mg PO once per day on days 1 to 4<br />
<br />
'''1-month cycle for 4 cycles'''<br />
<br />
====Subsequent treatment====<br />
*Responders: [[Multiple_myeloma,_consolidation_and_maintenance#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan, then autologous hematopoietic cell transplant]].''<br />
<br />
===Regimen variant #5, 100 -> 400 mg/day {{#subobject:24c0c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/21/1/16.full Weber et al. 2003]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 100 mg PO once per day on days 1 to 7, then 200 mg PO once per day on days 8 to 14, then 300 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 400 mg PO once per day <br />
*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
'''29-day cycles'''<br />
<br />
===Regimen variant #6, 200 mg/day {{#subobject:b1c11d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 17%"|Study<br />
!style="width: 15%"|Years of enrollment<br />
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 17%"|Comparator<br />
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[http://jco.ascopubs.org/content/20/21/4319.long Rajkumar et al. 2002]<br />
|NR<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[http://jco.ascopubs.org/content/24/3/431.long Rajkumar et al. 2005 (ECOG E1A00)]<br />
|2002-2003<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy|Dexamethasone]]<br />
|style="background-color:#91cf60"|Seems to have superior RR<br />
|style="background-color:#d73027"|Inferior toxicity<br />
|-<br />
|}<br />
''In ECOG E1A00 this regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.''<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 1 to 28<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd-numbered cycles: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
**Even-numbered cycles: 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002 Nov 1;20(21):4319-23. [http://jco.ascopubs.org/content/20/21/4319.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12409330 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12506164 PubMed]<br />
# '''Bologna 2002:''' Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, de Vivo A, Palareti G, Tura S, Baccarani M. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica. 2004 Jul;89(7):826-31. [http://www.haematologica.org/content/89/7/826.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15257934 PubMed]<br />
## '''Sub-analysis:''' Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005 Jul 1;106(1):35-9. Epub 2005 Mar 10. [http://www.bloodjournal.org/content/106/1/35 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15761019 PubMed]<br />
# '''ECOG E1A00:''' Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; [[Study_Groups#ECOG|ECOG]]. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006 Jan 20;24(3):431-6. Epub 2005 Dec 19. [http://jco.ascopubs.org/content/24/3/431.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/16365178 PubMed]<br />
# '''THAL-MM-003:''' Rajkumar SV, Rosiñol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, Olesnyckyj M, Yu Z, Knight R, Zeldis JB, Bladé J. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008 May 1;26(13):2171-7. Epub 2008 Mar 24. [http://jco.ascopubs.org/content/26/13/2171.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904367/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18362366 PubMed]<br />
# '''GIMEMA MM-BO2005:''' Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61424-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/21146205 PubMed] NCT01134484<br />
## '''Update:''' Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. [http://www.bloodjournal.org/content/120/1/9.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22498745 PubMed]<br />
## '''Update:''' Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, Galli M, Di Raimondo F, Crippa C, Boccadoro M, Barbato S, Tosi P, Narni F, Montefusco V, Testoni N, Spadano A, Terragna C, Pescosta N, Marzocchi G, Cellini C, Galieni P, Ronconi S, Gobbi M, Catalano L, Lazzaro A, De Sabbata G, Cangialosi C, Ciambelli F, Musto P, Elice F, Cavo M; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto Italian Myeloma Network). Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol. 2020 Dec;7(12):e861-e873. [https://doi.org/10.1016/s2352-3026(20)30323-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33242443 PubMed]<br />
# '''GEM05/MENOS65:''' Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; PETHEMA; GEM. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. [http://www.bloodjournal.org/content/120/8/1589.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22791289 PubMed] NCT00461747<br />
## '''Update:''' Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. [https://doi.org/10.1038/leu.2017.35 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28111466 PubMed]<br />
<br />
==TVAD doxil {{#subobject:6a10ab|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
TVAD doxil: '''<u>T</u>'''halidomide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin liposomal (Doxil), '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:71bc2d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm178 Zervas et al. 2007]<br />
|2002-2006<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#VAD_doxil|VAD doxil]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''This trial was open to patients aged 18 to 75 years old with previously untreated symptomatic MM and a life expectancy of greater than 6 months.''<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
====Chemotherapy====<br />
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1<br />
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
**Cycles 2 & 4: 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol. 2007 Aug;18(8):1369-75. [https://doi.org/10.1093/annonc/mdm178 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17693650 PubMed]<br />
<br />
==VAD doxil {{#subobject:6dfa10|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DVD: '''<u>D</u>'''oxil (Liposomal Doxorubicin), '''<u>V</u>'''incristine, '''<u>D</u>'''examethasone<br />
<br>DVd: '''<u>D</u>'''oxil (Liposomal Doxorubicin), '''<u>V</u>'''incristine, low-dose '''<u>d</u>'''examethasone<br />
<br>VAD doxil: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin liposomal (Doxil), '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1, indefinite ("DVd") {{#subobject:72393d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.21662/full Rifkin et al. 2006]<br />
|2001-2003<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[Multiple_myeloma_-_historical#VAD|VAd]]<br />
|style="background-color:#eeee01"|Non-inferior ORR<br />
|-<br />
|}<br />
''This regimen was intended for patients greater than or equal to 18 years and fulfilling a diagnosis of stage II or III MM according to the [[#Durie-Salmon_Staging_System_-_1975|Durie and Salmon criteria]].''<br />
====Chemotherapy====<br />
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> (maximum dose of 2 mg) IV over 5 minutes once on day 1<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, limited duration (4 cycles) {{#subobject:f03965|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdg287 Dimopoulos et al. 2003]<br />
|1999-2001<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR<br />
|-<br />
|[https://doi.org/10.1093/annonc/mdm178 Zervas et al. 2007]<br />
|2002-2006<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#TVAD_doxil|TVAD-Doxil]]<br />
|style="background-color:#fc8d59"|Seems to have inferior OS<br />
|-<br />
|}<br />
''Dimopoulos et al. 2003 was open to all patients with previously untreated multiple myeloma who were considered candidates for systemic treatment. Zervas et al. 2007 was open to patients aged 18 to 75 years old with previously untreated symptomatic MM and a life expectancy of greater than 6 months.''<br />
====Chemotherapy====<br />
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1<br />
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV over 60 minutes once on day 1<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
**Cycles 2 & 4: 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*In the cited Segeren et al. 1999 VAD protocol reference:<br />
*[[Fluconazole (Diflucan)]] 200 mg PO once per day <br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim/Sulfamethoxazole]] 960 mg (paper did not specify which component was 960 mg) PO twice per day for "prophylaxis"<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #3, limited duration (6 to 8 cycles) {{#subobject:121c56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.10946/full Hussein et al. 2002]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV once on day 1<br />
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1<br />
*[[Dexamethasone (Decadron)]] 40 mg IV or PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*Vitamin B6 200 mg PO once per day to help reduce risk of palmar-plantar erythrodysesthesia (PPE)<br />
<br />
'''28-day cycle for 6 to 8 cycles'''<br />
<br />
===References===<br />
# Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, Bukowski RM. A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer. 2002 Nov 15;95(10):2160-8. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.10946/full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12412170 PubMed]<br />
# Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol. 2003 Jul;14(7):1039-44. [https://doi.org/10.1093/annonc/mdg287 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/12853344 PubMed]<br />
# Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a phase III multicenter randomized trial. Cancer. 2006 Feb 15;106(4):848-58. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.21662/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16404741 PubMed]<br />
# Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol. 2007 Aug;18(8):1369-75. [https://doi.org/10.1093/annonc/mdm178 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17693650 PubMed]<br />
<br />
==VAD-P {{#subobject:9671a6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VAD-P: '''<u>Vi</u>'''ncristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone, '''<u>P</u>'''rednisone<br />
<br />
===Regimen {{#subobject:1e6b59|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/99/9/3163.long Berenson et al. 2002 (SWOG 9210)]<br />
|1993-1997<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#VAD-P.2FQ|VAD-P/Q]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Vincristine (Oncovin)]] 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg)<br />
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m<sup>2</sup>)<br />
**Poor-risk patients received 6.75 mg/m<sup>2</sup>/day in cycle 1 (total dose 27 mg/m<sup>2</sup>), with increase to full dose starting cycle 2 if no undue toxicity<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 50 mg PO once per day on days 9, 11, 13, 15, 17, 19<br />
<br />
'''21-day cycle for at least 9 cycles (6 months) or until at least 25% regression of disease'''<br />
<br />
====Subsequent treatment====<br />
*Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy: low-dose prednisone versus [[Multiple_myeloma_-_historical#Prednisone_monotherapy|high-dose prednisone]] maintenance<br />
<br />
===References===<br />
# '''SWOG 9210:''' Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. [http://www.bloodjournal.org/content/99/9/3163.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11964279 PubMed]<br />
<br />
==VAD-P/Q {{#subobject:5a391a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VAD-P/Q: '''<u>Vi</u>'''ncristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone, '''<u>P</u>'''rednisone, '''<u>Q</u>'''uinine<br />
<br />
===Regimen {{#subobject:9bebf1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/99/9/3163.long Berenson et al. 2002 (SWOG 9210)]<br />
|1993-1997<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#VAD-P|VAD-P]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Vincristine (Oncovin)]] 0.4 mg/day IV continuous infusion over 96 hours, started on day 2 (total dose per cycle: 1.6 mg)<br />
*[[Doxorubicin (Adriamycin)]] 9 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 2 (total dose per cycle: 36 mg/m<sup>2</sup>) <br />
**Poor-risk patients received 6.75 mg/m<sup>2</sup>/day in cycle 1 (total dose 27 mg/m<sup>2</sup>), with increase to full dose starting cycle 2 if no undue toxicity<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 2 to 5<br />
*[[Prednisone (Sterapred)]] 50 mg PO once per day on days 10, 12, 14, 16, 18, 20<br />
*[[Quinine (Qualaquin)]] 400 mg PO three times per day on days 1 to 6<br />
<br />
'''21-day cycle for at least 6 months or until at least 25% regression of disease'''<br />
====Subsequent treatment====<br />
*Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy: low-dose prednisone versus [[Multiple_myeloma_-_historical#Prednisone_monotherapy|high-dose prednisone]] maintenance<br />
<br />
===References===<br />
# '''SWOG 9210:''' Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. [http://www.bloodjournal.org/content/99/9/3163.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/11964279 PubMed]<br />
<br />
==VD {{#subobject:b2104f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib, '''<u>D</u>'''examethasone<br />
<br>Bd: '''<u>B</u>'''ortezomib, low-dose '''<u>d</u>'''examethasone<br />
<br>Bort-Dex: '''<u>Bort</u>'''ezomib, '''<u>Dex</u>'''amethasone<br />
<br>Vd: '''<u>V</u>'''elcade (Bortezomib), low-dose '''<u>d</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:59cfe6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://jco.ascopubs.org/content/33/33/3921.long Niesvizky et al. 2015 (UPFRONT)]<br />
|rowspan=2|2007-2010<br />
|rowspan=2 style="background-color:#1a9851"|Phase IIIb (E-de-esc)<br />
|1. [[#VMP|VMP]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#VTD|VTD]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''This regimen was meant for transplant ineligible patients.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Bortezomib_monotherapy|Bortezomib consolidation]]<br />
<br />
===Regimen variant #2 {{#subobject:6a8cb5|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/22/5752.full Moreau et al. 2011 (IFM 2007-02)]<br />
|2008-2009<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#VTD|vtD]]<br />
|style="background-color:#d73027"|Inferior VGPR rate<br />
|-<br />
|}<br />
''This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12<br />
**Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #3 {{#subobject:9d60fb|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/30/4621.long Harousseau et al. 2010 (IFM 2005-01)]<br />
|2005-2008<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|style="background-color:#d9ef8b"|Might have superior PFS<br />
|-<br />
|}<br />
''This regimen was intended for patients age less than or equal to 65 years with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 h).''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12 <br />
**Cycles 3 & 4: 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*One of the following bisphosphonates recommended:<br />
**[[Pamidronate (Aredia)]] 90 mg IV once every 4 weeks until first transplant<br />
**[[Zoledronic acid (Zometa)]] 4 mg IV once every 4 weeks until first transplant<br />
*"Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#DCEP|DCEP consolidation]] versus [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|high-dose melphalan with autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #4, weekly bortezomib {{#subobject:5f56bd|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13243/full Girnius et al. 2014 (X05153)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''35-day cycle for up to 6 cycles based on response and tolerance of side effects'''<br />
<br />
===References===<br />
<!-- Presented at the 48th Annual Meeting of the American Society of Hematology (ASH), December 9-12, 2006, Orlando, FL; the 49th Annual Meeting of the ASH, December 8-11, 2007, Atlanta, GA; the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 30-June 3, 2008, Chicago, IL; and the 2008 Annual Meeting of the American Society of Hematology ASH/ASCO Joint Symposium, December 7, 2008, San Francisco, CA. --><br />
# '''IFM 2005-01:''' Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. [http://jco.ascopubs.org/content/28/30/4621.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20823406 PubMed] NCT00200681<br />
## '''Subgroup analysis:''' Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guérin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L, Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S, Harousseau JL. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010 Oct 20;28(30):4630-4. Epub 2010 Jul 19. [http://jco.ascopubs.org/content/28/30/4630.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20644101 PubMed]<br />
# '''IFM 2007-02:''' Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. [http://www.bloodjournal.org/content/118/22/5752.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21849487 PubMed] NCT00910897<br />
# '''X05153:''' Girnius SK, Lee S, Kambhampati S, Rose MG, Mohiuddin A, Houranieh A, Zimelman A, Grady T, Mehta P, Behler C, Hayes TG, Efebera YA, Prabhala RH, Han A, Yellapragada SV, Klein CE, Roodman GD, Lichtenstein A, Munshi NC. A phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation. Br J Haematol. 2015 Apr;169(1):36-43. Epub 2015 Jan 8. Epub 2014 Sep 18. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13243/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25572917 PubMed]<br />
<!-- Presented at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011; and the 55th ASH Annual Meeting and Exposition, New Orleans, LA, December 7-10, 2013. --><br />
# '''UPFRONT:''' Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. [http://jco.ascopubs.org/content/33/33/3921.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26056177 PubMed]<br />
<br />
==VDC {{#subobject:f725ee|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>VDC-mod: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide ('''<u>mod</u>'''ified dose)<br />
<br>VCD: '''<u>V</u>'''elcade (Bortezomib), '''<u>C</u>'''yclophosphamide, '''<u>D</u>'''examethasone<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:eed411|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/21/2569.long Moreau et al. 2016 (IFM 2013-04)]<br />
|2013-2015<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|[[#VTD|VTD]]<br />
|style="background-color:#fc8d59"|Seems to have inferior ORR rate<br />
|-<br />
|}<br />
''This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg (route not specified) once per day on days 1 to 4, 9 to 12<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Autologous hematopoietic cell transplant, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center<br />
<br />
===Regimen variant #2, "VCD" {{#subobject:5f53d0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2015.80 Mai et al. 2015 (GMMG-MM5)]<br />
|2010-2012<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#PAD|PAD]]<br />
|style="background-color:#eeee01"|Non-inferior VGPR or better rate<br />
|-<br />
|}<br />
<br />
''This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 900 mg/m<sup>2</sup> IV once on day 1<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
<br />
====Supportive medications====<br />
*[[Trimethoprim-Sulfamethoxazole_(Bactrim_DS)|Cotrimoxazole]] (dose not specified)<br />
*[[Acyclovir (Zovirax)]] (dose not specified)<br />
*[[:Category:Bisphosphonates|Bisphosphonate]] IV every 4 weeks<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #3, "VDC" {{#subobject:c78302|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]<br />
|rowspan=2|2008-2009<br />
|rowspan=2 style="background-color:#1a9851"|Randomized Phase II (C)<br />
|1. [[#RVD|VDR]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|2. [[#RVDC|VDCR]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|}<br />
<br />
''This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a [[#Karnofsky_performance_scale|Karnofsky Performance Status]] greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. The only difference between this regimen and VDC-mod is the number of cyclophosphamide doses.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day <br />
**[[Warfarin (Coumadin)]] or [[Enoxaparin (Lovenox)]] could be used based on physician discretion<br />
*[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended<br />
*[[Acyclovir (Zovirax)]] prophylaxis for Herpes zoster recommended<br />
*[[:Category:Bisphosphonates|Bisphosphonates]] could be used "as necessary"<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Bortezomib_monotherapy|Bortezomib consolidation]]<br />
<br />
===Regimen variant #4, "VDC-mod" {{#subobject:a29211|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=3|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]<br />
|rowspan=3|2008-2009<br />
|rowspan=3 style="background-color:#91cf61"|Randomized Phase II, less than 20 in this arm (C)<br />
|1. [[#RVD|VDR]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|2. [[#RVDC|VDCR]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/VGPR rate<br />
|-<br />
|}<br />
''This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a [[#Karnofsky_performance_scale|Karnofsky Performance Status]] greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. This arm only had 17 patients enrolled; other arms of the EVOLUTION trial all had greater than 20 patients enrolled. The only difference between this and regimen #1 is the number of cyclophosphamide doses.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day <br />
**[[Warfarin (Coumadin)]] or [[Enoxaparin (Lovenox)]] could be used instead, based on physician discretion<br />
*[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended<br />
*[[Acyclovir (Zovirax)]] prophylaxis for Herpes zoster recommended<br />
*[[:Category:Bisphosphonates|Bisphosphonates]] could be used "as necessary"<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Bortezomib_monotherapy|Bortezomib consolidation]]<br />
<br />
===Regimen variant #5, "CyBorD", once per week bortezomib {{#subobject:d82b2d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/115/16/3416.long Reeder et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
''This regimen was described in a letter to the editor of Blood.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 <br />
**Cycles 3 & 4: 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===Regimen variant #6, "CyBorD" {{#subobject:3f805b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711213/ Reeder et al. 2009]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton pump inhibitors|Proton pump inhibitor (PPI)]]<br />
*[[Acyclovir (Zovirax)]]<br />
*[[:Category:Fluoroquinolone|Quinolone antibiotic]]<br />
*Antifungal mouthwash recommended<br />
<br />
'''28-day cycle for 4 to 12 cycles'''<br />
<br />
===References===<br />
# Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, Noble B, Pirooz NA, Spong JE, Piza JG, Zepeda VH, Mikhael JR, Leis JF, Bergsagel PL, Fonseca R, Stewart AK. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009 Jul;23(7):1337-41. Epub 2009 Feb 19. [https://doi.org/10.1038/leu.2009.26 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2711213/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19225538 PubMed]<br />
# Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, Hentz J, Pirooz NA, Piza JG, Tiedemann R, Mikhael JR, Bergsagel PL, Leis JF, Fonseca R, Stewart AK. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010 Apr 22;115(16):3416-7. [http://www.bloodjournal.org/content/115/16/3416.long link to original letter] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20413666 PubMed]<br />
<!-- Presented in abstract form at the 51st American Society of Hematology (ASH) annual meeting, New Orleans, LA, December 7, 2009; the 52nd ASH annual meeting, Orlando, FL, December 6, 2010; and the 13th International Myeloma Workshop, Paris, France, May 5, 2011.--><br />
# Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22422823 PubMed]<br />
# '''Meta-Analysis:''' Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/24861981 PubMed]<br />
# '''GMMG-MM5:''' Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. [https://doi.org/10.1038/leu.2015.80 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25787915 PubMed]<br />
## '''Subgroup analysis:''' Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Weisel K, Duerig J, Goldschmidt H. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015 Jul;100(7):964-9. Epub 2015 Apr 3. [http://www.haematologica.org/content/100/7/964.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486231/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25840597 PubMed]<br />
# '''IFM 2013-04:''' Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. [http://www.bloodjournal.org/content/127/21/2569.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27002117 PubMed] NCT01564537<br />
<br />
==VMP {{#subobject:c029ec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMP: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone<br />
<br>MPV: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>V</u>'''elcade (Bortezomib)<br />
===Regimen variant #1, 4 cycles {{#subobject:916d56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/108/7/2165.long Mateos et al. 2006]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
''Note: this was the phase II portion of this phase I/II study.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''42-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#VMP|VMP consolidation]]<br />
<br />
===Regimen variant #2, 6 cycles, bi-weekly bortezomib {{#subobject:64da89|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(09)00398-X/abstract Gasparetto et al. 2009]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 7, '''given at least 1 hour prior to bortezomib'''<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 7<br />
<br />
====Supportive medications====<br />
*[[:Category:Bisphosphonates|Bisphosphonates]] recommended<br />
*[[Acyclovir (Zovirax)]] (dose not specified) recommended<br />
<br />
'''28-day cycle for up to 6 cycles'''; treatment could be given beyond 6 cycles at investigator discretion<br />
<br />
===Regimen variant #3, 6 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 5 {{#subobject:48440e|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext Mateos et al. 2010 (GEM2005)]<br />
|2006-2008<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#VTP|VTP]]<br />
|style="background-color:#91cf60"|Seems to have superior OS (*)<br />
|-<br />
|}<br />
''This regimen was intended for patients with untreated multiple myeloma, 65 years and older. Efficacy is based on the 2014 update.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycle 1: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32 <br />
**Cycles 2 to 5: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]<br />
*Prophylactic [[Acyclovir (Zovirax)|aciclovir]] was recommended.<br />
<br />
'''42-day cycle for 1 cycle, then 35-day cycle for 5 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#VP|VP]] versus [[Multiple_myeloma,_consolidation_and_maintenance#VT|VT]] maintenance<br />
<br />
===Regimen variant #4, 8 cycles {{#subobject:b06c6b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://jco.ascopubs.org/content/33/33/3921.long Niesvizky et al. 2015 (UPFRONT)]<br />
|rowspan=2|2007-2010<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#VD|VD]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#VTD|VTD]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''This regimen was meant for transplant ineligible patients.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] as follows:<br />
**Cycles 1, 3, 5, 7: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]]<br />
**Cycles 1, 3, 5, 7: 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''21-day cycle for 8 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Bortezomib_monotherapy|Bortezomib consolidation]]<br />
<br />
===Regimen variant #5, 9 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 8 {{#subobject:9994d0|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1714678 Mateos et al. 2017 (ALCYONE)]<br />
|2015-2016<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Dara-VMP|Dara-VMP]]<br />
|style="background-color:#d73027"|Inferior OS (*)<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older. Reported efficacy is based on the 2019 update.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycle 1: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32<br />
**Cycles 2 to 9: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 22, 29<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''42-day cycle for 9 cycles'''<br />
<br />
===Regimen variant #6, 9 cycles, bi-weekly bortezomib x 4, then weekly bortezomib x 5 {{#subobject:5c31d4|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa0801479 San Miguel et al. 2008 (VISTA)]<br />
|2004-2006<br />
|style="background-color:#1a9851"|Phase III (E-RT-esc)<br />
|[[Multiple_myeloma_-_historical#MP|MP]]<br />
|style="background-color:#1a9850"|Superior OS<br />
|-<br />
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010 (GIMEMA MM-03-05)]<br />
|2006-2009<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#VMPT|VMPT-VT]]<br />
|style="background-color:#fc8d59"|Seems to have inferior OS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123433/ San-Miguel et al. 2014 (CR015901)]<br />
|2009-2011<br />
|style="background-color:#1a9851"|Randomized Phase II (C)<br />
|VMP & Siltuximab<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR rate<br />
|-<br />
|[http://www.bloodjournal.org/content/133/18/1953.long Facon et al. 2019 (CLARION)]<br />
|2013-2015<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#KMP|KMP]]<br />
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
''In GIMEMA MM-03-05, VISTA, and CLARION this regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 to 4: 1.3 mg/m<sup>2</sup> IV or SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32<br />
**Cycles 5 to 9: 1.3 mg/m<sup>2</sup> IV or SC once per day on days 1, 8, 22, 29<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Bisphosphonates|Bisphosphonates]] given to patients with myeloma-associated bone disease unless contraindicated (only mentioned in San Miguel et al. 2008)<br />
<br />
'''42-day cycle for 9 cycles'''<br />
<br />
===Regimen variant #7, 9 cycles, weekly bortezomib {{#subobject:2eb356|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010 (GIMEMA MM-03-05)]<br />
|2006-2009<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#VMPT|VMPT-VT]]<br />
|style="background-color:#fc8d59"|Seems to have inferior OS<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions. This dosing is the result of a mid-protocol amendment.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''35-day cycle for 9 cycles'''<br />
<br />
===References===<br />
# Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006 Oct 1;108(7):2165-72. Epub 2006 Jun 13. [http://www.bloodjournal.org/content/108/7/2165.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16772605 PubMed] <br />
## '''Update:''' Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Garcia-Sanchez P, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, Alegre A, de Arriba F, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica. 2008 Apr;93(4):560-5. Epub 2008 Mar 5. [http://www.haematologica.org/content/93/4/560.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18322252 PubMed] <br />
# '''VISTA:''' San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. [https://www.nejm.org/doi/full/10.1056/NEJMoa0801479 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/18753647 PubMed]<br />
## '''Update:''' Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010 May 1;28(13):2259-66. Epub 2010 Apr 5. [http://jco.ascopubs.org/content/28/13/2259.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20368561 PubMed] <br />
## '''Update:''' San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. [http://jco.ascopubs.org/content/31/4/448.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23233713 PubMed] <br />
# Gasparetto C, Gockerman JP, Diehl LF, de Castro CM, Moore JO, Long GD, Horwitz ME, Keogh G, Chute JP, Sullivan KM, Neuwirth R, Davis PH, Sutton LM, Anderson RD, Chao NJ, Rizzieri D. "Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma. Biol Blood Marrow Transplant. 2010 Jan;16(1):70-7. Epub 2009 Sep 3. [http://www.bbmt.org/article/S1083-8791(09)00398-X/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19733251 PubMed]<br />
# Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20739218 PubMed]<br />
## '''Subgroup analysis:''' Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. [http://www.bloodjournal.org/content/118/17/4547.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/21900193 PubMed]<br />
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. [http://www.bloodjournal.org/content/120/13/2581 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22889759 PubMed]<br />
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators?. Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. [http://www.bloodjournal.org/content/124/12/1887 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25102853 PubMed]<br />
# '''GIMEMA MM-03-05:''' Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. [http://jco.ascopubs.org/content/28/34/5101.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20940200 PubMed]<br />
## '''Post-hoc analysis:''' Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. [http://www.bloodjournal.org/content/116/23/4745.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20807892 PubMed]<br />
## '''Subgroup analysis:''' Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/22/5759.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/21951682 PubMed]<br />
## '''Update:''' Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. [http://jco.ascopubs.org/content/32/7/634.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24449241 PubMed]<br />
# '''CR015901:''' San-Miguel J, Bladé J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, Robak T, Prasad SV, Tee Goh Y, Laubach J, Spencer A, Mateos MV, Palumbo A, Puchalski T, Reddy M, Uhlar C, Qin X, van de Velde H, Xie H, Orlowski RZ. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood. 2014 Jun 26;123(26):4136-42. Epub 2014 May 15. Erratum in: Blood. 2014 Aug 14;124(7):1201. [http://www.bloodjournal.org/content/123/26/4136.long link to original article] '''refers to protocol in [https://www.nejm.org/doi/full/10.1056/NEJMoa0801479 San Miguel et al. 2008]''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123433/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24833354 PubMed]<br />
<!-- Presented at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011; and the 55th ASH Annual Meeting and Exposition, New Orleans, LA, December 7-10, 2013. --><br />
# '''UPFRONT:''' Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. [http://jco.ascopubs.org/content/33/33/3921.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26056177 PubMed]<br />
# '''ALCYONE:''' Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1714678 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29231133 PubMed]<br />
## '''Update:''' Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Krevvata M, Chen Y, Wang J, Kudva A, Ukropec J, Wroblewski S, Qi M, Kobos R, San-Miguel J. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2019 Dec 10. [Epub ahead of print] [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32956-3/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/31836199 PubMed]<br />
# '''CLARION:''' Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos M, Hajek R, Pour L, Jurczyszyn A, Qiu L, Klippel Z, Zahlten-Kumeli A, Osman M, Paiva B, San-Miguel J. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019 May 2;133(18):1953-1963. Epub 2019 Feb 28. [http://www.bloodjournal.org/content/133/18/1953.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30819926 PubMed]<br />
<br />
==VMP, then Rd {{#subobject:adb844|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMP, then Rd: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, followed by '''<u>R</u>'''evlimid (Lenalidomide), low dose '''<u>d</u>'''examethasone<br />
<br />
===Protocol {{#subobject:9bda27|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/4/420.long Mateos et al. 2015 (PETHEMA GEM05)]<br />
|2005-NR<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#VMP.2FRd|VMP/Rd]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS18<br />
|-<br />
|}<br />
''This regimen was intended for patients aged greater than or equal to 65 years with newly diagnosed, untreated, symptomatic, measurable MM.''<br />
<br />
====VMP portion====<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycle 1: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32<br />
**Cycles 2 to 9: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''42-day cycle for 1 cycle, then 28-day cycle for 8 cycles'''<br />
<br />
====Rd portion====<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Supportive medications====<br />
*During [[Bortezomib (Velcade)|bortezomib]] therapy:<br />
**[[:Category:Bisphosphonates|Bisphosphonates]] <br />
**[[:Category:Antivirals |Prophylactic antiviral therapy]]<br />
*During [[Lenalidomide (Revlimid)|lenalidomide]] therapy:<br />
**Mandatory thromboprophylaxis: [[Aspirin]] or [[:Category:Low_molecular_weight_heparins |low–molecular weight heparin]]<br />
<br />
===References===<br />
# '''PETHEMA GEM05:''' Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. [http://www.bloodjournal.org/content/127/4/420.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26500339 PubMed] NCT00443235<br />
<br />
==VMP/Rd {{#subobject:765398|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMP/Rd: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone alternating with '''<u>R</u>'''evlimid (Lenalidomide), low dose '''<u>d</u>'''examethasone<br />
<br />
===Protocol {{#subobject:fd772b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/4/420.long Mateos et al. 2015 (PETHEMA GEM05)]<br />
|2005-NR<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|[[#VMP.2C_then_Rd|VMP, then Rd]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS18<br />
|-<br />
|}<br />
''This regimen was intended for patients aged greater than or equal to 65 years with newly diagnosed, untreated, symptomatic, measurable MM.''<br />
<br />
====Chemotherapy, VMP portion, first cycle====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32 <br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''42-day cycle for 1 cycle, then Rd cycle #1:'''<br />
<br />
====Chemotherapy, VMP portion, remaining cycles====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22 <br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 8 cycles, alternating with Rd:'''<br />
<br />
====Chemotherapy, Rd portion====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle alternating with VMP x 9 cycles'''<br />
<br />
====Supportive medications====<br />
*During [[Bortezomib (Velcade)|bortezomib]] therapy:<br />
**[[:Category:Bisphosphonates|Bisphosphonates]] <br />
**[[:Category:Antivirals |Prophylactic antiviral therapy]]<br />
*During [[Lenalidomide (Revlimid)|lenalidomide]] therapy:<br />
**Mandatory thromboprophylaxis: [[Aspirin]] or [[:Category:Low_molecular_weight_heparins |low–molecular weight heparin]]<br />
<br />
===References===<br />
# '''PETHEMA GEM05:''' Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. [http://www.bloodjournal.org/content/127/4/420.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26500339 PubMed] NCT00443235<br />
<br />
==VMPT {{#subobject:6b6370|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMPT: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>T</u>'''halidomide<br />
<br />
===Regimen variant #1 {{#subobject:cb90b1|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010 (GIMEMA MM-03-05)]<br />
|2006-2009<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#VMP|VMP]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 to 4: 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32 <br />
**Cycles 5 to 9: 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 22, 29<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 42<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''42-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#VT|VT maintenance]]<br />
<br />
===Regimen variant #2 {{#subobject:5cdd9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010 (GIMEMA MM-03-05)]<br />
|2006-2009<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#VMP|VMP]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant represents a mid-protocol change (in 2007) where cycle length was decreased from 6 to 5 weeks and bortezomib was changed to weekly dosing.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once per day on days 1, 8, 15, 22<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 42<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''35-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#VT|VT maintenance]]<br />
<br />
===References===<br />
# '''GIMEMA MM-03-05:''' Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. [http://jco.ascopubs.org/content/28/34/5101.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20940200 PubMed]<br />
## '''Post-hoc analysis:''' Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. [http://www.bloodjournal.org/content/116/23/4745.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20807892 PubMed]<br />
## '''Subgroup analysis:''' Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/22/5759.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/21951682 PubMed]<br />
## '''Update:''' Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. [http://jco.ascopubs.org/content/32/7/634.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24449241 PubMed]<br />
<br />
==VTD {{#subobject:dbab97|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VTD: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br>vTD: low-dose '''<u>v</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:eed411|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/21/2569.long Moreau et al. 2016 (IFM 2013-04)]<br />
|2013-2015<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|[[#VDC|VCD]]<br />
|style="background-color:#91cf60"|Seems to have superior ORR rate<br />
|-<br />
|}<br />
''This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
*[[Dexamethasone (Decadron)]] 40 mg (route not specified) once per day on days 1 to 4, 9 to 12<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Autologous hematopoietic cell transplant, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center<br />
<br />
===Regimen variant #2 {{#subobject:b082c7|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://jco.ascopubs.org/content/33/33/3921.long Niesvizky et al. 2015 (UPFRONT)]<br />
|rowspan=2|2007-2010<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#VD|VD]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|2. [[#VMP|VMP]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
<br />
''This regimen was intended for patients with newly diagnosed, symptomatic, measurable MM requiring systemic therapy, and who were ineligible for stem-cell transplantation because of age (greater than or equal to 65 years), comorbidities, or personal preference.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5<br />
<br />
'''21-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Bortezomib_monotherapy|Bortezomib consolidation]]<br />
<br />
===Regimen variant #3 {{#subobject:6f69a9|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/31/2/247.long Ludwig et al. 2012 (26866138-MMY-2043)]<br />
|2007-2008<br />
|style="background-color:#1a9851"|Randomized Phase II (C)<br />
|[[Stub#VTDC|VTDC]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of nCR or better rate<br />
|-<br />
|}<br />
''This regimen was intended for patients aged 18 to 70 years with previously untreated, measurable MM requiring systemic therapy, who were candidates for high-dose chemotherapy and autologous hematopoietic cell transplant.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*Patients who remained eligible for transplant: [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic cell transplant]]<br />
*Transplant ineligible patients or patients achieving CR could undergo 4 additional cycles of VTD<br />
<br />
===Regimen variant #4 {{#subobject:18f973|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://www.bloodjournal.org/content/120/8/1589.long Rosiñol et al. 2012 (GEM05/MENOS65)]<br />
|rowspan=2|2006-2009<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E-esc)<br />
|1. [[#TD|TD]]<br />
|style="background-color:#91cf60"|Seems to have superior PFS<br />
|-<br />
|2. [[Multiple_myeloma_-_historical#VBMCP.2FVBAD|VBMCP/VBAD]], then B<br />
|style="background-color:#91cf60"|Seems to have superior PFS<br />
|-<br />
|}<br />
''This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were 65 years of age or younger with measurable serum and/or urine M protein.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28 <br />
**Cycles 2 to 6: 200 mg PO once per day on days 1 to 28<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|Low molecular weight heparin (LMWH)]] or [[Aspirin]] recommended<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #5, "vTD" {{#subobject:788138|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/22/5752.full Moreau et al. 2011 (IFM 2007-02)]<br />
|2008-2009<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#VD|VD]]<br />
|style="background-color:#1a9850"|Superior VGPR rate<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ Lok et al. 2014]<br />
|2011-2013<br />
|style="background-color:#91cf61"|Non-randomized<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|}<br />
''IFM 2007-02 was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours). Lok et al. 2014 uses the same dosing except that bortezomib is given SC.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV or SC once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12<br />
**Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic cell transplant]]<br />
<br />
===Regimen variant #6 {{#subobject:ac1b9a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961424-9/fulltext Cavo et al. 2010 (GIMEMA MM-BO2005)]<br />
|2006-2008<br />
|style="background-color:#1a9851"|Phase III (E-esc)<br />
|[[#TD|TD]]<br />
|style="background-color:#1a9850"|Superior OS (*)<br />
|-<br />
|}<br />
''This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma. Reported efficacy is based on the 2020 update.''<br />
<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21 <br />
**Cycles 2 & 3: 200 mg PO once per day on days 1 to 21 <br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
<br />
'''21-day cycle for 3 cycles'''<br />
====Subsequent treatment====<br />
*[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem MEL200 with auto HSCT]], with interim Thal-Dex maintenance (see paper for details)<br />
<br />
===Regimen variant #7 {{#subobject:4901ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.25143/full Kaufman et al. 2010]<br />
|style="background-color:#ffffbe"|Retrospective<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] prophylaxis to decrease risk of DVTs<br />
*Prophylactic "treatment with antiviral and antibiotic medications"<br />
<br />
'''21-day cycle for 3 to 4 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman JL, Nooka A, Vrana M, Gleason C, Heffner LT, Lonial S. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer. 2010 Jul 1;116(13):3143-51. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.25143/full link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/20564642 PubMed]<br />
# '''GIMEMA MM-BO2005:''' Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961424-9/fulltext link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/21146205 PubMed] NCT01134484<br />
## '''Update:''' Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. [http://www.bloodjournal.org/content/120/1/9.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22498745 PubMed]<br />
## '''Update:''' Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, Galli M, Di Raimondo F, Crippa C, Boccadoro M, Barbato S, Tosi P, Narni F, Montefusco V, Testoni N, Spadano A, Terragna C, Pescosta N, Marzocchi G, Cellini C, Galieni P, Ronconi S, Gobbi M, Catalano L, Lazzaro A, De Sabbata G, Cangialosi C, Ciambelli F, Musto P, Elice F, Cavo M; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto Italian Myeloma Network). Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol. 2020 Dec;7(12):e861-e873. [https://doi.org/10.1016/s2352-3026(20)30323-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33242443 PubMed]<br />
# '''IFM 2007-02:''' Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. [http://www.bloodjournal.org/content/118/22/5752.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21849487 PubMed] NCT00910897<br />
# '''GEM05/MENOS65:''' Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; PETHEMA; GEM. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. [http://www.bloodjournal.org/content/120/8/1589.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22791289 PubMed] NCT00461747<br />
## '''Update:''' Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. [https://doi.org/10.1038/leu.2017.35 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28111466 PubMed]<br />
<!-- Presented in part at the 51st Annual Meeting of the American Society of Hematology, New Orleans, LA, December 5-8, 2009, and the 50th Annual Meeting of the European Hematology Association, Barcelona, Spain, June 10-13, 2010. --><br />
# '''26866138-MMY-2043:''' Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Ricci D, Cakana A, Enny C, Feng H, van de Velde H, Harousseau JL. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013 Jan 10;31(2):247-55. Epub 2012 Oct 22. [http://jco.ascopubs.org/content/31/2/247.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23091109 PubMed] NCT00531453<br />
## '''Update:''' Ludwig H, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Chaturvedi S, Ataman O, Enny C, Feng H, van de Velde H, Viterbo L. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol. 2015 Nov;171(3):344-54. Epub 2015 Jul 7. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13582/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758383/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26153365 PubMed]<br />
# Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous bortezomib incorporated into the bortezomib-thalidomide-dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. [http://www.haematologica.org/content/99/3/e33.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24532044 PubMed]<br />
# '''Meta-Analysis:''' Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/24861981 PubMed]<br />
<!-- Presented at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011; and the 55th ASH Annual Meeting and Exposition, New Orleans, LA, December 7-10, 2013. --><br />
# '''UPFRONT:''' Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. [http://jco.ascopubs.org/content/33/33/3921.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26056177 PubMed]<br />
# '''IFM 2013-04:''' Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. [http://www.bloodjournal.org/content/127/21/2569.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27002117 PubMed] NCT01564537<br />
<br />
==VTP {{#subobject:56d6fe|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VTP: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>P</u>'''rednisone<br />
<br />
===Regimen {{#subobject:f707bc|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext Mateos et al. 2010 (GEM2005)]<br />
|2006-2008<br />
|style="background-color:#1a9851"|Phase III (E-switch-ooc)<br />
|[[#VMP|VMP]]<br />
|style="background-color:#fc8d59"|Seems to have inferior OS (*)<br />
|-<br />
|}<br />
''This regimen was intended for patients with untreated multiple myeloma, 65 years and older. Efficacy is based on the 2014 update.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycle 1: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day on days 1 to 15, then 100 mg PO once per day on days 16 to 42<br />
**Cycles 2 to 6: 100 mg PO once per day<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]<br />
*Prophylactic [[Acyclovir (Zovirax)|aciclovir]] was recommended.<br />
*Thromboprophylaxis: [[Aspirin]] or [[:Category:Low_molecular_weight_heparins|low-molecular-weight heparin]]<br />
<br />
'''42-day cycle for 1 cycle, then 35-day cycle for 5 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#VP|VP]] versus [[Multiple_myeloma,_consolidation_and_maintenance#VT|VT]] maintenance<br />
<br />
===References===<br />
# '''GEM2005:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20739218 PubMed]<br />
## '''Subgroup analysis:''' Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. [http://www.bloodjournal.org/content/118/17/4547.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/21900193 PubMed]<br />
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. [http://www.bloodjournal.org/content/120/13/2581 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22889759 PubMed]<br />
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators?. Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. [http://www.bloodjournal.org/content/124/12/1887 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25102853 PubMed]<br />
<br />
==Zoledronic acid therapy {{#subobject:78cd0d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:39fa9f|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ Morgan et al. 2010 (MRC Myeloma IX)]<br />
|2003-2007<br />
|style="background-color:#1a9851"|Phase III (E-switch-ic)<br />
|Clodronic acid<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this agent was not given as monotherapy, but is included separately from the regimens that it was given with, based on the RCT design.''<br />
====Supportive therapy====<br />
*[[Zoledronic acid (Zometa)]] as follows:<br />
**During induction: 4 mg IV over 15 minutes once every 3 to 4 weeks<br />
**Consolidation onwards: 4 mg IV over 15 minutes once every 4 weeks<br />
<br />
'''Continued indefinitely'''<br />
===References===<br />
# '''MRC Myeloma IX:''' Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62051-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131037 PubMed] ISRCTN68454111<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. [http://www.bloodjournal.org/content/118/5/1231.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152492/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21652683 PubMed]<br />
## '''Update:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22021371 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. [http://www.haematologica.org/content/97/3/442.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291601/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22058209 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. [http://clincancerres.aacrjournals.org/content/19/21/6030.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/23995858 PubMed]<br />
<br />
=First-line therapy (including transplant ineligible), non-randomized or retrospective data=<br />
''Note: most but not all multiple myeloma first-line regimens specify whether patients are transplant eligible, or not. We will begin to break this section in those respective subsections.''<br />
<br />
==BBD {{#subobject:c09648|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BBD: '''<u>B</u>'''endamustine, '''<u>B</u>'''ortezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:c9fe76|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.14536/abstract Berdeja et al. 2017 (SCRI MM 23)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
''Note: this is the modified treatment schema.''<br />
====Chemotherapy====<br />
*[[Bendamustine]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 2, 8, 9, 15, 16<br />
<br />
====Supportive medications====<br />
*Mandatory VZV prophylaxis<br />
<br />
'''28-day cycle for 8 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#VD|Bortezomib & Dexamethasone maintenance]]<br />
<br />
===References===<br />
# '''SCRI MM 23:''' Berdeja JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA Jr, Boccia RV, Donnellan W, Flinn I. Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J Haematol. 2017 Apr;177(2):254-262. Epub 2017 Feb 7. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14536/abstract link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28169430 PubMed]<br />
<br />
==BiRd {{#subobject:4ea159|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
BiRd: '''<u>Bi</u>'''axin, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:d718cd|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/111/3/1101.long Niesvizky et al. 2007]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Clarithromycin (Biaxin)]] as follows:<br />
**Cycle 1: 500 mg PO twice per day on days 2 to 28 <br />
**Cycle 2 onwards: 500 mg PO twice per day on days 1 to 28<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Cycle 1: 25 mg PO once per day on days 3 to 21 <br />
**Cycle 2 onwards: 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycle 1: 40 mg PO once per day on days 1, 2, 3, 8, 15, 22 <br />
**Cycle 2 onwards: 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg PO once per day <br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day <br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] PO twice per day, 3 times a week<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S, Jalbrzikowski J, Pearse RN, Zafar F, Pekle K, Larow A, Lent R, Mark T, Cho HJ, Shore T, Tepler J, Harpel J, Schuster MW, Mathew S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008 Feb 1;111(3):1101-9. Epub 2007 Nov 7. [http://www.bloodjournal.org/content/111/3/1101.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/17989313 PubMed]<br />
## '''Update:''' Rossi A, Mark T, Jayabalan D, Christos P, Zafar F, Pekle K, Pearse R, Chen-Kiang S, Coleman M, Niesvizky R. BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood. 2013 Mar 14;121(11):1982-1985. Epub 2013 Jan 8. [http://www.bloodjournal.org/content/121/11/1982.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596960/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23299315 PubMed]<br />
# '''Retrospective:''' Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. [http://dx.doi.org/10.1002/ajh.21777 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956597/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20645430 PubMed]<br />
<br />
==CRd {{#subobject:fdc431|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:ccb917|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901994/ Kumar et al. 2011 (RV-MM-PI-0116)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] or [[Warfarin (Coumadin)]] for patients with history of thrombotic events or at "higher" risk<br />
<br />
'''28-day cycle for 4 to 12 cycles'''<br />
====Subsequent treatment====<br />
*At physician discretion, patient could proceed to [[Multiple_myeloma,_consolidation_and_maintenance#Lenalidomide_monotherapy|lenalidomide maintenance]] +/- dexamethasone, after the 12th cycle, until progression<br />
<br />
===References===<br />
# '''RV-MM-PI-0116:''' Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, Laumann K, Greipp PR, Lust JA, Gertz MA, Zeldenrust SR, Bergsagel PL, Reeder CB, Witzig TE, Fonseca R, Russell SJ, Mikhael JR, Dingli D, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol. 2011 Aug;86(8):640-5. '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901994/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21630308 PubMed]<br />
<br />
==CYKLONE {{#subobject:0c91d6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CYKLONE: '''<u>C</u>'''yclophosphamide, '''<u>K</u>'''yprolis (Carfilzomib), Tha'''<u>L</u>'''lidomide, Dexamethas'''<u>ONE</u>'''<br />
<br />
===Regimen {{#subobject:cf729e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521972/ Mikhael et al. 2015 (MC0982)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
<br />
''The carfilzomib dose here is the MTD dose, tested in N=29 patients. The authors state that patients could proceed to autologous hematopoietic cell transplant after four cycles but do not provide criteria to undergo transplant as opposed to continuing CYKLONE.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Carfilzomib (Kyprolis)]] as follows:<br />
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16<br />
**Cycle 2 onwards: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 28<br />
*[[Dexamethasone (Decadron)]] 40 mg PO on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] or [[:Category:Low_molecular_weight_heparins|LMWH]] for patients intolerant of aspirin<br />
*[[Acyclovir (Zovirax)]] 400 mg PO twice per day<br />
*[[:Category:Antibacterials|Antibacterials]] (not further specified)<br />
*250 to 500 ml of IVF prior to cycle 1 doses of [[Carfilzomib (Kyprolis)]] and then only for patients "at risk for tumor lysis syndrome" in subsequent cycles<br />
<br />
'''28-day cycle for 4 to 12 cycles (see note)'''<br />
===References===<br />
# '''MC0982:''' Mikhael JR, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, Mayo A, Nagi Reddy SK, Gano K, Dueck AC, Stewart AK. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015 Apr;169(2):219-27. Epub 2015 Feb 13. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13296/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521972/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25683772 PubMed]<br />
<br />
==IRd {{#subobject:74c2a1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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IRd: '''<u>I</u>'''xazomib, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:6b49cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71125-8/abstract Kumar et al. 2014 (C16005)]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
<br />
''This is the MTD dose of this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 12 cycles''' <br />
====Subsequent treatment====<br />
*Transplant-eligible patients could proceed to [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|autologous hematopoietic cell transplant]] after 6 cycles<br />
*Patients who did not undergo transplant proceeded to [[Multiple_myeloma,_consolidation_and_maintenance#Ixazomib_monotherapy|ixazomib maintenance]] after the 12th cycle<br />
<br />
===References===<br />
<!-- Presented at ASH 2012 and ASH 2014, Abstract 82: Long-Term Ixazomib Maintenance Is Tolerable and Improves Depth of Response Following Ixazomib-Lenalidomide-Dexamethasone Induction in Patients (Pts) with Previously Untreated Multiple Myeloma (MM): Phase 2 Study Results --><br />
# '''C16005:''' Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71125-8/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/25456369 PubMed]<br />
<br />
==KCD {{#subobject:a634d0|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
KCD: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>C</u>'''yclophosphamide, '''<u>D</u>'''examethasone<br />
<br>CCyd: '''<u>C</u>'''arfilzomib, '''<u>Cy</u>'''clophosphamide, '''<u>d</u>'''examethasone<br />
<br>KCyd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>Cy</u>'''clophosphamide, '''<u>d</u>'''examethasone<br />
===Regimen variant #1, bi-weekly carfilzomib {{#subobject:c2c7b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/124/1/63 Bringhen et al. 2014 (IST-CAR-506)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Carfilzomib (Kyprolis)]] as follows:<br />
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1 & 2 then 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16<br />
**Cycles 2 to 9: 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Carfilzomib_monotherapy|Carfilzomib maintenance]]<br />
<br />
===Regimen variant #2, weekly carfilzomib ("wKCyd") {{#subobject:148a16|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2017.327 Bringhen et al. 2017 (IST-CAR-561)]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
''Note: this is the MTD established for the phase II portion of the trial.''<br />
====Targeted therapy====<br />
*[[Carfilzomib (Kyprolis)]] 70 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Carfilzomib_monotherapy|Carfilzomib maintenance]]<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Palumbo, Antonio; Bringhen, Sara; Villani, Oreste; Siniscalchi, Agostina; Russo, Eleonora; Uccello, Giuseppina; Cerrato, Chiara; Gilestro, Milena; Rossi, Davide; Boccadoro, Mario. Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients. ASH Annual Meeting Abstracts 2012 120: 730 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/730 link to abstract] --><br />
# '''IST-CAR-506:''' Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. [http://www.bloodjournal.org/content/124/1/63 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/24855212 PubMed]<br />
# '''IST-CAR-561:''' Bringhen S, D'Agostino M, De Paoli L, Montefusco V, Liberati AM, Galieni P, Grammatico S, Muccio VE, Esma F, De Angelis C, Musto P, Ballanti S, Offidani M, Petrucci MT, Gaidano G, Corradini P, Palumbo A, Sonneveld P, Boccadoro M. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018 Apr;32(4):979-985. Epub 2017 Nov 16. [https://doi.org/10.1038/leu.2017.327 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/29263440 PubMed]<br />
<br />
==KTD {{#subobject:48ff6b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
KTd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:d87119|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ Sonneveld et al. 2014 (CARTHADEX)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
<br />
''Three cohorts are reported; optimal dose of carfilzomib is not described.''<br />
====Targeted therapy====<br />
*[[Carfilzomib (Kyprolis)]] as follows:<br />
**Cycle 1: 20 mg/m<sup>2</sup> IV once per day on days 1 & 2, and:<br />
**''Cohort 1:'' 27 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles<br />
**''Cohort 2:'' 36 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles<br />
**''Cohort 3:'' 45 mg/m<sup>2</sup> IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|High-dose melphalan with stem cell rescue]]<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Pieter Sonneveld, Emilie Asselberg-Hacker, Sonja Zweegman, Bronno van der Holt, Marie Jose Kersten, Edo Vellenga, Marinus van Marwijk Kooy, Okke de Weerdt, Sarah Lonergan, Antonio Palumbo, Henk Lokhorst. Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network. Blood Nov 2013,122(21)688 [http://www.bloodjournal.org/content/122/21/688 link to abstract] --><br />
# '''CARTHADEX:''' Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. [http://www.bloodjournal.org/content/125/3/449 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25398935 PubMed]<br />
<br />
==PAD doxil {{#subobject:55d959|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
PAD doxil: '''<u>P</u>'''S-341 (Bortezomib), liposomal '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone<br />
<br>DVD: '''<u>D</u>'''oxil (Liposomal doxorubicin), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone<br />
<br>VDD: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''oxil (Liposomal doxorubicin), '''<u>D</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:57cebe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08884.x/full Berenson et al. 2011]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Pegylated liposomal doxorubicin (Doxil)]] 5 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg IV once per day on days 1, 4, 8, 11<br />
<br />
'''28-day cycle for up to 8 cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:aaa1e3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/5/800.long Palumbo et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Targeted therapy====<br />
*[[Pegylated liposomal doxorubicin (Doxil)]] 30 mg/m<sup>2</sup> IV once on day 4<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18 <br />
**Cycles 2 to 4: 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Acyclovir (Zovirax)]] recommended during [[Bortezomib (Velcade)]] therapy<br />
<br />
'''21-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Tandem_melphalan.2C_then_auto_HSCT|Tandem MEL-100, then auto HSCT]]<br />
<br />
===Regimen variant #3 {{#subobject:e38e22|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/30/5015.long Jakubowiak et al. 2009]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
====Targeted therapy====<br />
*[[Pegylated liposomal doxorubicin (Doxil)]] 30 mg/m<sup>2</sup> IV once on day 4<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycle 1: 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12 <br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
<br />
====Supportive medications====<br />
*Low-molecular weight heparin 40 mg SC once per day or [[Aspirin]] 81 mg PO once per day for DVT prophylaxis<br />
*[[Acyclovir (Zovirax)]] 400 mg PO twice per day for Herpes zoster prophylaxis<br />
<br />
'''21-day cycle for 6 cycles'''<br />
<br />
===References===<br />
# Jakubowiak AJ, Kendall T, Al-Zoubi A, Khaled Y, Mineishi S, Ahmed A, Campagnaro E, Brozo C, Braun T, Talpaz M, Kaminski MS. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009 Oct 20;27(30):5015-22. Epub 2009 Sep 8. [http://jco.ascopubs.org/content/27/30/5015.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19738129 PubMed]<br />
## '''Update:''' Dytfeld D, Griffith KA, Friedman J, Lebovic D, Harvey C, Kaminski MS, Jakubowiak AJ. Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. Leuk Lymphoma. 2011 Jul;52(7):1271-80. [https://www.tandfonline.com/doi/full/10.3109/10428194.2011.567316 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21699382 PubMed]<br />
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. [http://jco.ascopubs.org/content/28/5/800.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20048187 PubMed]<br />
## '''Update:''' Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. [http://www.bloodjournal.org/content/122/8/1376.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23775712 PubMed]<br />
# Berenson JR, Yellin O, Chen CS, Patel R, Bessudo A, Boccia RV, Yang HH, Vescio R, Yung E, Mapes R, Eades B, Hilger JD, Wirtschafter E, Hilger J, Nassir Y, Swift RA. A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol. 2011 Dec;155(5):580-7. Epub 2011 Sep 26. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2011.08884.x/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21950583 PubMed]<br />
<br />
==RP {{#subobject:583b2a|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
RP: '''<u>R</u>'''evlimid (Lenalidomide) & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:9d35d3|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.271 Falco et al. 2012]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
''Note: this is a component of the sequential "RP-MPR-RP" protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Prednisone (Sterapred)]] 50 mg PO three times per week<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day, taken during [[Lenalidomide (Revlimid)]] treatment (unclear from protocol if this also means off weeks)<br />
*Antiviral prophylaxis if history of VZV.<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#MPR|MPR consolidation]]<br />
<br />
===References===<br />
# Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. [https://doi.org/10.1038/leu.2012.271 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22996335 PubMed]<br />
<br />
==Total Therapy {{#subobject:06fc58|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Protocol {{#subobject:1cd95c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/89/3/789.long Barlogie et al. 1997 (Total Therapy 1)]<br />
|style="background-color:#91cf61"|Prospective<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa053583 Barlogie et al. 2006 (Total Therapy 2)]<br />
| style="background-color:#1a9851" |Prospective with randomization<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06639.x/full Barlogie et al. 2007 (Total Therapy 3)]<br />
|style="background-color:#91cf61"|Prospective<br />
|-<br />
|}<br />
''Total Therapy is a very complicated protocol, you are highly recommended to refer to the original manuscripts for further details. Total Therapy 3 is replicated here; the references for Total Therapy 2 are provided below but there are no plans to add this regimen here, for now.''<br />
<br />
====Induction (VTD-PACE)====<br />
VTD-PACE: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone, '''<u>P</u>'''latinum (Cisplatin), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 4 to 7<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 4 to 7<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m<sup>2</sup>)<br />
*[[Doxorubicin (Adriamycin)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m<sup>2</sup>)<br />
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 1600 mg/m<sup>2</sup>)<br />
*[[Etoposide (Vepesid)]] 40 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 160 mg/m<sup>2</sup>)<br />
*Peripheral blood stem cells (PBSC) are usually collected during cycle 1--cycle 2 PBSC collection is done if needed--with a median CD34 count of 29 x 10<sup>6</sup>/kg. 87% of collections yielded at least 20 x 10<sup>6</sup>/kg.<br />
<br />
'''Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart'''<br />
<br />
During the interim period between cycle 1 and cycle 2, as well as after cycle 2 and prior to transplant, this is given once platelets have recovered to at least 50 x 10<sup>9</sup>/L:<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 21<br />
<br />
'''21-day cycles, given between induction cycles and transplant'''<br />
<br />
In other words, the initial therapy consists of: Induction therapy cycle 1, dexamethasone & thalidomide, induction therapy cycle 2, dexamethasone & thalidomide, then transplant.<br />
<br />
====Supportive medications====<br />
*As described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.<br />
*[[Filgrastim (Neupogen)]] "was administered to support induction and consolidation chemotherapy regimens"<br />
*"Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed<br />
*Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide<br />
<br />
====Chemotherapy, autologous hematopoietic cell transplant====<br />
''Full details were not provided in Barlogie et al. 2007. Tandem autologous transplants were done between 2 to 6 months apart.<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup><br />
<br />
During the interim period after transplant 1 and transplant 2, patients receive:<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day on days 1 to 21<br />
<br />
'''21-day cycles, given in the time between and after each transplant'''; if platelets less than 50 x 10<sup>9</sup>/L, proceed to year 1 of maintenance therapy. Otherwise, if platelets are at least 50 x 10<sup>9</sup>/L, proceed to consolidation therapy.<br />
<br />
====Consolidation (VTD-PACE)====<br />
VTD-PACE: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone, '''<u>P</u>'''latinum (Cisplatin), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide<br />
<br />
''Cycle 1 of consolidation starts 1.5 to 4 months after the last transplant. Cycle 2 of consolidation starts 2 to 4 months after cycle 1 of consolidation.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 7.5 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 30 mg/m<sup>2</sup>)<br />
*[[Doxorubicin (Adriamycin)]] 7.5 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 30 mg/m<sup>2</sup>)<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1200 mg/m<sup>2</sup>)<br />
*[[Etoposide (Vepesid)]] 30 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 120 mg/m<sup>2</sup>)<br />
<br />
'''2 cycles total are given according to the interval specified above, with the interim therapy below used'''<br />
<br />
During the interim period between cycle 1 and cycle 2, as well as after cycle 2 and prior to maintenance therapy, this is given once platelets have recovered to at least 50 x 10<sup>9</sup>/L:<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21<br />
<br />
'''21-day cycles, given between consolidation cycles and maintenance'''<br />
<br />
In other words, consolidation therapy consists of: Consolidation therapy cycle 1, dexamethasone & thalidomide, consolidation therapy cycle 2, dexamethasone & thalidomide, then maintenance therapy.<br />
<br />
====Supportive medications====<br />
*As described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.<br />
*[[Filgrastim (Neupogen)]] "was administered to support induction and consolidation chemotherapy regimens"<br />
*"Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed<br />
*Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide<br />
<br />
====Maintenance year 1 (VTD)====<br />
VTD: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
''Year 1 of maintenance therapy starts 1 to 4 months after consolidation cycle 2.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 28<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 8 to 11<br />
<br />
'''28-day cycle for 13 cycles (1 year)''', then proceed to maintenance therapy years 2 to 3<br />
<br />
====Maintenance years 2 & 3 (TD)====<br />
TD: '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once every other day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 26 cycles (2 years)'''<br />
<br />
===References===<br />
# '''Total Therapy 1:''' Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. [http://www.bloodjournal.org/content/89/3/789.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/9028309 PubMed]<br />
## '''Update:''' Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. [http://www.bloodjournal.org/content/93/1/55.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/9864146 PubMed]<br />
## '''Pooled update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20085933 PubMed]<br />
# '''Total Therapy 2:''' Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, Fassas A, Zangari M, Hollmig K, Pineda-Roman M, Lee C, Talamo G, Thertulien R, Kiwan E, Krishna S, Fox M, Crowley J. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006 Mar 9;354(10):1021-30. [https://www.nejm.org/doi/full/10.1056/NEJMoa053583 link to original article] '''supportive medication details''' [https://pubmed.ncbi.nlm.nih.gov/16525139 PubMed]<br />
## '''Update:''' Zangari M, van Rhee F, Anaissie E, Pineda-Roman M, Haessler J, Crowley J, Barlogie B. Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of Total Therapy 1. Br J Haematol. 2008 May;141(4):433-44. Epub 2008 Mar 26. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2008.06982.x/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649864/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18371114 PubMed]<br />
## '''Subgroup analysis:''' Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K, Alsayed Y, Waheed S, Petty N, Epstein J, Shaughnessy JD Jr, Tricot G, Zangari M, Zeldis J, Barer S, Crowley J. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008 Oct 15;112(8):3115-21. Epub 2008 May 20. [http://www.bloodjournal.org/content/112/8/3115.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2569166/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18492953 PubMed]<br />
## '''Pooled update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20085933 PubMed]<br />
# '''Total Therapy 3:''' Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of Total Therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06639.x/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17593024 PubMed]<br />
## '''Update:''' Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, Crowley J, Shaughnessy JD Jr, Barlogie B. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol. 2008 Mar;140(6):625-34. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06921.x/full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655432/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18302711 PubMed]<br />
## '''Pooled update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20085933 PubMed]<br />
<br />
==VP {{#subobject:8cd2dc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VP: '''<u>V</u>'''elcade (Bortezomib) & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:19553c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2016.36 Larocca et al. 2016]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Prednisone (Sterapred)]] 50 mg PO once every other day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma,_consolidation_and_maintenance#Bortezomib_monotherapy_2|Bortezomib maintenance]]<br />
<br />
===References===<br />
# Larocca A, Bringhen S, Petrucci MT, Oliva S, Falcone AP, Caravita T, Villani O, Benevolo G, Liberati AM, Morabito F, Montefusco V, Passera R, De Rosa L, Omedé P, Vincelli ID, Spada S, Carella AM, Ponticelli E, Derudas D, Genuardi M, Guglielmelli T, Nozzoli C, Aghemo E, De Paoli L, Conticello C, Musolino C, Offidani M, Boccadoro M, Sonneveld P, Palumbo A. A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma. Leukemia. 2016 Jun;30(6):1320-6. [https://doi.org/10.1038/leu.2016.36 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26898189 PubMed]<br />
<br />
==VTD-PACE {{#subobject:539ce9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VTD-PACE: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone, '''<u>P</u>'''latinum (Cisplatin), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide<br />
<br />
===Regimen {{#subobject:b0b58e|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06639.x/full Barlogie et al. 2007 (Total Therapy 3)]<br />
|style="background-color:#91cf61"|Prospective<br />
|-<br />
|}<br />
<br />
''Note: this is the induction therapy used in Total Therapy 3. We are not aware of other sources prospectively describing VTD-PACE.''<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day on days 4 to 7<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 4 to 7<br />
====Chemotherapy====<br />
*[[Cisplatin (Platinol)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m<sup>2</sup>)<br />
*[[Doxorubicin (Adriamycin)]] 10 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m<sup>2</sup>)<br />
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 1600 mg/m<sup>2</sup>)<br />
*[[Etoposide (Vepesid)]] 40 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 160 mg/m<sup>2</sup>)<br />
<br />
'''Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart'''<br />
<br />
===References===<br />
# '''Total Therapy 3:''' Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of Total Therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. [https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2007.06639.x/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17593024 PubMed]<br />
<section end=1st-line /><br />
{{#lst:Multiple myeloma|bottom}}<br />
[[Category:Multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46454Light-chain (AL) amyloidosis2020-10-22T16:03:45Z<p>Samuelrubinstein: /* References */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1 to 2: 16 mg/kg SQ once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg SQ once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''ANDROMEDA (abstract):''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46453Light-chain (AL) amyloidosis2020-10-22T16:03:18Z<p>Samuelrubinstein: /* Dara-CyBorD {{#subobject:1dca0c|Regimen=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab, '''<u>C</u>'''yclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1 to 2: 16 mg/kg SQ once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg SQ once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''ANDROMEDA abstract''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46452Light-chain (AL) amyloidosis2020-10-22T16:03:05Z<p>Samuelrubinstein: /* Chemotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab, '''<u>C</u>'''Cyclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1 to 2: 16 mg/kg SQ once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg SQ once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg</sup> PO once per day on days 1, 8, 15, 22<br />
<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''ANDROMEDA abstract''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46451Light-chain (AL) amyloidosis2020-10-22T16:02:38Z<p>Samuelrubinstein: /* Regimen {{#subobject:e15b5d|Variant=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab, '''<u>C</u>'''Cyclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1 to 2: 16 mg/kg SQ once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg SQ once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg</sup> PO once per day on days 2 to 4<br />
<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''ANDROMEDA abstract''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
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<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
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M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
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MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
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MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46450Light-chain (AL) amyloidosis2020-10-22T16:01:37Z<p>Samuelrubinstein: /* Regimen {{#subobject:e15b5d|Variant=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab, '''<u>C</u>'''Cyclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract:</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate (*)<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1 to 2: 16 mg/kg SQ once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg SQ once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg</sup> PO once per day on days 2 to 4<br />
<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''ANDROMEDA abstract''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46449Light-chain (AL) amyloidosis2020-10-22T16:01:15Z<p>Samuelrubinstein: /* Regimen {{#subobject:e15b5d|Variant=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab, '''<u>C</u>'''Cyclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> Abstract</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate (*)<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1 to 2: 16 mg/kg SQ once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg SQ once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg</sup> PO once per day on days 2 to 4<br />
<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''ANDROMEDA abstract''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46448Light-chain (AL) amyloidosis2020-10-22T16:00:53Z<p>Samuelrubinstein: /* References */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab, '''<u>C</u>'''Cyclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> ABSTRACT</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate (*)<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1 to 2: 16 mg/kg SQ once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg SQ once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg</sup> PO once per day on days 2 to 4<br />
<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''ANDROMEDA abstract''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=46447Light-chain (AL) amyloidosis2020-10-22T16:00:21Z<p>Samuelrubinstein: </p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>University of North Carolina<br>Chapel Hill, NC</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
|1976-1983<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Dara-CyBorD {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
Dara-CyBorD: '''<u>Dara</u>'''tumumab, '''<u>C</u>'''Cyclophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:e15b5d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis '''<b> ABSTRACT</b>''' Kastritis et al. 2020 (ANDROMEDA)]<br />
|2017-2020<br />
|style="background-color:#1a9851"|Randomized Phase II (E-RT-esc)<br />
|[[#VDC|CyBorD]]<br />
|style="background-color:#1a9850"|Superior complete hematologic response rate (*)<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycle 1 to 2: 16 mg/kg SQ once per day on days 1, 8, 15, 22<br />
**Cycles 3 to 6: 16 mg/kg SQ once per day on days 1 & 22<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg</sup> PO once per day on days 2 to 4<br />
<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Daratumumab_monotherapy|Daratumumab maintenance]] x 2 years<br />
<br />
===References===<br />
# '''ANDROMEDA ABSTRACT''' Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schonland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, HJungria V, Wong SW, Rosenzweig M, Bumma N, Chauveau D, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schechter JM, Weiss BM, Vermeulen J, Merlini G, Comenzo RL. Subcutaneous Daratumumab + Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in patients with mewly diagnosed light chain (AL) amyloidosis: primary results from the phase 3 ANDROMEDA study. 25th EHA Congress. Frankfurt. 2020. [https://library.ehaweb.org/eha/2020/eha25th/303396/efstathios.kastritis.subcutaneous.daratumumab.2B.cyclophosphamide.bortezomib.html?f=listing%3D0%2Abrowseby%3D8%2Asortby%3D1%2Amedia%3D3%2Ace_id%3D1766%2Asearch%3Ddaratumumab%2Bamyloidosis link to abstract] <br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
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M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1, BSA-based melphalan {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2, weight-based melphalan {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
|1999-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#VMD|BMDex]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
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MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
|NR<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
|rowspan=2|1982-1992<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
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MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br>BMDex: '''<u>B</u>'''ortezomib, '''<u>M</u>'''elphalan, '''<u>Dex</u>'''amethasone<br />
===Regimen variant #1, 8 cycles {{#subobject:objab2|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://doi.org/10.1200/jco.20.01285 Kastritis et al. 2020 (EMN-03)]<br />
|2011-2016<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|MDex]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|}<br />
''Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.''<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
**Cycles 3 to 8: 1.3 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 2 cycles, then 35-day cycle for 6 cycles'''<br />
<br />
===Regimen variant #2, 20 cycles {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
# '''EMN-03:''' Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. [https://doi.org/10.1200/jco.20.01285 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32730181 PubMed] NCT01277016<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Case series<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable sortable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|Years of enrollment<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
|1994-2002<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
|2000-2005<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
|2007-2011<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
|2009-2012<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*NCT822, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed] NCT00344526<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed] NCT01998503<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1038/leu.2012.274 Landau et al. 2012 (NCT822)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# '''NCT822:''' Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://doi.org/10.1038/leu.2012.274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
====Targeted therapy====<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
====Targeted therapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Targeted therapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Targeted therapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Targeted therapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=User:Samuelrubinstein&diff=46444User:Samuelrubinstein2020-10-22T15:17:47Z<p>Samuelrubinstein: Updated bio</p>
<hr />
<div>[[File:Samuelrubinstein.jpg|thumb|Samuel Rubinstein, MD]]<br />
Samuel Rubinstein MD is a Clinical Assistant Professor of Medicine in the Division of Hematology at the University of North Carolina-Chapel Hill Lineberger Comprehensive Cancer Center. His current research focuses on exploring outcomes and conducting clinical trials for patients with plasma cell dyscrasias including multiple myeloma and AL amyloidosis. He is also the site PI at UNC for the COVID-19 and Cancer Consortium (CCC-19). He is the HemOnc.org page editor for [[Light-chain (AL) amyloidosis]] and Smoldering Multiple Myeloma.</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=45069Light-chain (AL) amyloidosis2020-07-15T02:00:10Z<p>Samuelrubinstein: </p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://pubmed.ncbi.nlm.nih.gov/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://pubmed.ncbi.nlm.nih.gov/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
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M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1 {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2 {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article][https://pubmed.ncbi.nlm.nih.gov/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed]<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
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MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to original article] [https://pubmed.ncbi.nlm.nih.gov/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
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MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://pubmed.ncbi.nlm.nih.gov/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed]<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|[http://www.haematologica.org/content/104/11/2274 Minnema et al. 2019 (HOVON 104)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 80%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed]<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
#'''HOVON 104:''' Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. [http://www.haematologica.org/content/104/11/2274 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/30923094/ PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html Landau et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html Landau et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In Landau et al. 2012, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*Landau et al. 2012, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html Landau et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Landau et al. 2012, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*Landau et al. 2012, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17855669 PubMed]<br />
# Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/24386911 PubMed]<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html Landau et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://doi.org/10.1200/JCO.19.01721 Lentzsch et al. 2020 (AAAJ7800)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> IV once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# '''AAAJ7800:''' Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21 [Epub ahead of print] [https://doi.org/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Chemotherapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Chemotherapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Chemotherapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Light-chain_(AL)_amyloidosis&diff=42945Light-chain (AL) amyloidosis2020-02-24T15:26:12Z<p>Samuelrubinstein: /* Relapsed or refractory */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
=Guidelines=<br />
==[http://www.b-s-h.org.uk/ BSH]==<br />
*'''2014:''' Wechalekar et al. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13155/abstract Guidelines on the management of AL amyloidosis] [https://www.ncbi.nlm.nih.gov/pubmed/25303672 PubMed]<br />
<br />
==EMN==<br />
*'''2018:''' Gavriatopoulou et al. [https://www.nature.com/articles/s41375-018-0209-7 European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias] [https://www.ncbi.nlm.nih.gov/pubmed/30038381 PubMed]<br />
<br />
==[https://www.nccn.org/ NCCN]==<br />
*[https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf NCCN Guidelines - Systemic Light Chain Amyloidosis]<br />
<br />
=First-line therapy (including transplant ineligible)=<br />
<br />
==Colchicine monotherapy {{#subobject:06983b|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9ee4f6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|[https://www.amjmed.com/article/0002-9343(87)90222-1/pdf Cohen et al. 1987]<br />
| style="background-color:#91cf61" |Non-randomized<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#MP|MP]]<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Colchicine (Colcrys)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/3934968 PubMed]<br />
# Cohen AS, Rubinow A, Anderson JJ, Skinner M, Mason JH, Libbey C, Kayne H. Survival of patients with primary (AL) amyloidosis: colchicine-treated cases from 1976 to 1983 compared with cases seen in previous years (1961 to 1973). Am J Med. 1987 Jun;82(6):1182-90. [https://www.amjmed.com/article/0002-9343(87)90222-1/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3605135 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9110907 PubMed]<br />
<br />
==CRd {{#subobject:4bee23|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>Cy</u>'''clophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>LDC: '''<u>L</u>'''enalidomide, '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide <br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br />
===Regimen variant #1, "LDC" {{#subobject:8bba62|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] as follows:<br />
**Cycles 1 to 6: 300 mg/m<sup>2</sup> IV once per day on days 1 & 8<br />
**Cycles 7 to 12: 300 mg/m<sup>2</sup> IV once on day 1<br />
*[[Lenalidomide (Revlimid)]] as follows:<br />
**Normal eGFR: 15 mg PO once per day on days 1 to 21<br />
**eGFR greater than 30 mL/min/1.73m<sup>2</sup> but less than 50 mL/min/1.73m<sup>2</sup>: 10 mg PO once per day on days 1 to 21<br />
**eGFR less than 30 mL/min/1.73m<sup>2</sup>: 5 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12<br />
**Cycles 7 to 12: 20 mg PO once per day on days 1 to 4<br />
**Cardiac stage III (this is not defined): upfront modification "allowed" but not defined<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day, or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
====Subsequent treatment====<br />
*Patients without progression who were tolerating therapy: [[#Rd|Rd maintenance]]<br />
<br />
===Regimen variant #2, "CRd" {{#subobject:d4c970|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis as follows:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*"Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===Regimen variant #3, "RdC" {{#subobject:92db93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This was the highest dose level tested in Kastritis et al. 2012, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22504925 PubMed]<br />
<!-- no pre-pub disclosed --><br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22517904 PubMed]<br />
# Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA cooperative study group. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25974382 PubMed]<br />
<br />
==CTD {{#subobject:c079c5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:4605b4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:b049b0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
<!-- no pre-pub disclosed --><br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16990593 PubMed]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1dca0c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, 15 mg dosing {{#subobject:3b9f18|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg (physician discretion) PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued indefinitely<br />
<br />
===Regimen variant #2, 25 mg dosing {{#subobject:f71995|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
====Subsequent treatment====<br />
*If no response after 3 cycles of therapy, then patients were escalated to [[#Rd_2|lenalidomide & dexamethasone]]. Otherwise, treatment continued up to 12 cycles<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16960148 PubMed]<br />
## '''Update:''' Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. [http://www.bloodjournal.org/content/116/11/1990.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20847211 PubMed]<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17008538 PubMed]<br />
<br />
==M-DEX {{#subobject:c07166|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
M-DEX: '''<u>M</u>'''elphalan & '''<u>DEX</u>'''amethasone<br />
===Regimen variant #1 {{#subobject:ce6a1b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan, then auto HSCT]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 10 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] three times per week<br />
<br />
'''1-month cycle for up to 18 cycles'''<br />
<br />
''Patients achieving complete hematologic remission could stop treatment after 12 cycles.''<br />
<br />
===Regimen variant #2 {{#subobject:ad7105|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/103/8/2936.long Palladini et al. 2003]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.22 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day on days 1 to 10<br />
*[[Ciprofloxacin (Cipro)]] 250 mg PO twice per day on days 1 to 10<br />
*[[Itraconazole (Sporanox)]] 100 mg PO once per day on days 1 to 10<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
# Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. [http://www.bloodjournal.org/content/103/8/2936.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/15070667 PubMed]<br />
## '''Update:''' Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. [http://www.bloodjournal.org/content/110/2/787.long link to original article][https://www.ncbi.nlm.nih.gov/pubmed/17606766 PubMed]<br />
## '''Update:''' Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. [http://www.haematologica.org/content/99/4/743.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3971085/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24213149 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17855669 PubMed]<br />
<br />
==MP {{#subobject:946da1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:b1471a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/52/4/818.long Kyle et al. 1978]<br />
| style="background-color:#1a9851" |Randomized (E-esc)<br />
|Placebo<br />
| style="background-color:#91cf60" |Longer time on treatment<br />
|-<br />
|[http://www.amjmed.com/article/0002-9343(85)90521-2/pdf Kyle et al. 1985]<br />
| style="background-color:#1a9851" |Randomized (E-switch-ooc)<br />
|[[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
| rowspan="2" |[https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 Kyle et al. 1997]<br />
| rowspan="2" style="background-color:#1a9851" |Phase III (C)<br />
|1. [[#Colchicine_monotherapy|Colchicine]]<br />
| style="background-color:#1a9850" |Superior OS<br />
|-<br />
|2. Melphalan, Prednisone, Colchicine<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
''Of historic interest.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] <br />
*[[Prednisone (Sterapred)]]<br />
<br />
===References===<br />
# Kyle RA, Greipp PR. Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood. 1978 Oct;52(4):818-27. [http://www.bloodjournal.org/content/52/4/818.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/356916 PubMed]<br />
# Kyle RA, Greipp PR, Garton JP, Gertz MA. Primary systemic amyloidosis: comparison of melphalan/prednisone versus colchicine. Am J Med. 1985 Dec;79(6):708-16. [http://www.amjmed.com/article/0002-9343(85)90521-2/pdf link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/3934968 PubMed]<br />
# Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 1997 Apr 24;336(17):1202-7. [https://www.nejm.org/doi/full/10.1056/NEJM199704243361702 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9110907 PubMed]<br />
<br />
==MRD {{#subobject:159853|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
MRD: '''<u>M</u>'''elphalan, '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>L-M-Dex: '''<u>L</u>'''enalidomide, '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, "L-M-Dex" {{#subobject:301867|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.haematologica.org/content/102/8/1424 Hegenbart et al. 2017]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
''Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Melphalan (Alkeran)]] 0.15 mg/kg PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 6 cycles'''<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis with ONE of the following:<br />
**Standard patients: [[Aspirin]] 100 mg PO once per day <br />
**Patients with a history of VTE or thrombophilia: [[:Category:Low molecular weight heparins|low-molecular weight heparin]] (dose/schedule not specified)<br />
<br />
===Regimen variant #2 {{#subobject:3310f2|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ Sanchorwala et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 5 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day to decrease risk of [[Lenalidomide (Revlimid)]]-associated venous thromboembolism (VTE)<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]] to decrease risk of gastritis from [[Dexamethasone (Decadron)]]<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:7d51af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/116/23/4777.long Moreau et al. 2010]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins|LMWH]] for the first 4 cycles, then [[Aspirin]] as another option if no thrombosis<br />
<br />
'''28-day cycle for up to 9 cycles'''<br />
<br />
===References===<br />
<!-- This work has been presented previously at the 51st American Society of Hematology annual meeting, New Orleans, December 7, 2009, oral presentation, abstract 427; and the XIIth International Symposium on Amyloidosis, Rome, Italy, April 21, 2010, oral presentation, abstract 86. --><br />
# Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. [http://www.bloodjournal.org/content/116/23/4777.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20724537 PubMed]<br />
# Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. [http://www.haematologica.org/content/98/5/789.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640126/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23144200 PubMed]<br />
# Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. [http://www.haematologica.org/content/102/8/1424 link to original article] '''contains verified protocol'''[https://www.ncbi.nlm.nih.gov/pubmed/28522573 PubMed]<br />
<br />
==No induction==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
| style="background-color:#1a9851" |Randomized Phase II (C)<br />
|[[#VD|BD]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No induction prior to transplant.''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24386911 PubMed]<br />
<br />
==VD {{#subobject:33ab5d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>examethasone<br />
===Regimen variant #1, lower-dose dex {{#subobject:23d6a1|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 4, 8, 11<br />
<br />
====Supportive medications====<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
*[[:Category:Antivirals|Antiviral medication]]<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Bortezomib_.26_Melphalan.2C_then_auto_HSCT|Bortezomib & high-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===Regimen variant #2, higher-dose dex {{#subobject:1b0b57|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
| style="background-color:#1a9851" |Randomized Phase II (E-esc)<br />
|[[#No_induction|No induction]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
<br />
===References===<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24386911 PubMed]<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25858810 PubMed]<br />
<br />
==VDC {{#subobject:d1f835|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VDC: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
<br>CyBorD: '''<u>Cy</u>'''clophosphamide, '''<u>Bor</u>'''tezomib, '''<u>D</u>'''examethasone<br />
===Regimen variant #1, 300/1.3/40 {{#subobject:8d1a0b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===Regimen variant #2, 300/1.5/40 {{#subobject:9e2799|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ Mikhael et al. 2012]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
''Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> PO once per day on days 1, 8, 15, 22<br />
*[[Bortezomib (Velcade)]] 1.5 mg/m<sup>2</sup> SC once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[:Category:Antivirals|Antiviral]] prophylaxis<br />
<br />
'''28-day cycle for 2 to 6 cycles'''<br />
<br />
===References===<br />
# '''Retrospective:''' Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. [http://www.bloodjournal.org/content/119/19/4391.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3557400/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22331188 PubMed]<br />
# '''Retrospective:''' Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. [http://www.haematologica.org/content/99/9/1479.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4562537/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24859879 PubMed]<br />
# '''Retrospective:''' Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. [http://www.bloodjournal.org/content/126/5/612.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25987656 PubMed]<br />
<br />
==VMD {{#subobject:ce3e96|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VMD: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>D</u>'''examethasone<br />
<br />
===Regimen {{#subobject:f500cb|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://ash.confex.com/ash/2009/webprogram/Paper24495.html Zonder et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows, '''given first''':<br />
**No peripheral neuropathy at baseline: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
**Peripheral neuropathy at baseline: 1 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] as follows, '''given third'''<br />
**Serum creatinine up to 2.5 mg/dL: 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
**Serum creatinine greater than 2.5 mg/dL: 6 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Dexamethasone (Decadron)]] as follows, '''given second'''<br />
**Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22<br />
**Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''4- to 6-week cycle for up to 20 cycles'''<br />
<br />
===References===<br />
# '''Abstract:''' Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. [http://ash.confex.com/ash/2009/webprogram/Paper24495.html link to abstract]<br />
<br />
=Consolidation after first-line therapy=<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:5426f4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, HDM 140 mg/m<sup>2</sup> {{#subobject:c0ec02|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
===Regimen variant #2, HDM 200 mg/m<sup>2</sup> {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext Sanchorawala et al. 2015 (X05292)]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#c4c4c4" |HRR: 77%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#VD|Bortezomib & Dexamethasone]] x 2 <br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> IV once per day on days -6, -3, +1, +4<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===References===<br />
# '''X05292:''' Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. [http://www.bbmt.org/article/S1083-8791(15)00230-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25858810 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:34c98c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen variant #1, 100 mg/m<sup>2</sup> {{#subobject:01c7af|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html Landau et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
|-<br />
|}<br />
''Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.''<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cell re-infused on day not specified'''<br />
====Subsequent treatment====<br />
*Less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #2, 140 mg/m<sup>2</sup> {{#subobject:a7075d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html Landau et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In Landau et al. 2012, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*Landau et al. 2012, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===Regimen variant #3, 200 mg/m<sup>2</sup> {{#subobject:418872|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://annals.org/article.aspx?articleid=717091 Skinner et al. 2004]<br />
| style="background-color:#91cf61" |Phase II<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa070484 Jaccard et al. 2007]<br />
| style="background-color:#1a9851" |Phase III (E-esc)<br />
|[[#M-DEX|M-DEX]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html Landau et al. 2012]<br />
| style="background-color:#ffffbe" |Phase II, <20 pts<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ Huang et al. 2014 (NJCT-0703)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|}<br />
''Note: in Landau et al. 2012, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.''<br />
====Preceding treatment====<br />
*NJCT-0703: [[#VD|BD]] x 2 versus [[#No_induction|no induction]]<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day 0<br />
<br />
'''Stem cell re-infused on day 2'''<br />
====Subsequent treatment====<br />
*Landau et al. 2012, less than CR: [[#VD_2|BD consolidation]] x 6<br />
===References===<br />
# Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. [http://annals.org/article.aspx?articleid=717091 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/14734330 PubMed]<br />
# Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; Myélome Autogreffe (MAG) and Intergroupe Francophone du Myélome (IFM) Intergroup. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. [https://www.nejm.org/doi/full/10.1056/NEJMoa070484 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17855669 PubMed]<br />
# Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23014566 PubMed]<br />
# '''NJCT-0703:''' Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. [http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-12-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895846/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24386911 PubMed]<br />
<br />
==VD {{#subobject:ccdebb|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
<br>BD: '''<u>B</u>'''ortezomib & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:c63d93|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html Landau et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]], with less than CR<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Cycles 2 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
'''21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)'''<br />
===References===<br />
# Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. [https://www.nature.com/leu/journal/v27/n4/full/leu2012274a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23014566 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
==Rd {{#subobject:adfbd2|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>Len</u>'''alidomide & '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:066689|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full Cibeira et al. 2015 (LENDEXAL)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#CRd|LDC]] x 12<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day or [[:Category:Low_molecular_weight_heparins|Low molecular weight heparin]]<br />
<br />
'''28-day cycle for 39 cycles (3 years)'''<br />
<br />
===References===<br />
# '''LENDEXAL:''' Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA cooperative study group. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13500/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25974382 PubMed]<br />
<br />
=Relapsed or refractory=<br />
==Bendamustine & Dexamethasone {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01721 Lentzsch et al. 2020]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Bendamustine]] 100 mg/m<sup>2</sup> once per day on days 1 & 2<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for up to 6 cycles or progression of disease''' <br />
<br />
===References===<br />
# Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 Feb 21:JCO1901721. doi: 10.1200/JCO.19.01721. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01721 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/32083996 PubMed]<br />
<br />
==Bortezomib monotherapy {{#subobject:2518e6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen variant #1, twice per week {{#subobject:b37e74|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (route not specified) once per day on days 1, 4, 8, 11<br />
<br />
'''21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===Regimen variant #2, weekly schedule {{#subobject:5be0b9|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/118/4/865.long Reece et al. 2011 (CAN2007)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit'''<br />
<br />
===References===<br />
<!--<br />
# Reece DE, Sanchorawala V, Hegenbart U, Merlini G, Palladini G, Fermand JP, Vescio RA, Liu X, Elsayed YA, Cakana A, Comenzo RL; VELCADE CAN2007 Study Group. Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood. 2009 Aug 20;114(8):1489-97. Epub 2009 Jun 4. [http://www.bloodjournal.org/content/114/8/1489.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19498019 PubMed] content property of [http://hemonc.org HemOnc.org]<br />
# '''Retrospective:''' Kastritis E, Wechalekar AD, Dimopoulos MA, Merlini G, Hawkins PN, Perfetti V, Gillmore JD, Palladini G. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J Clin Oncol. 2010 Feb 20;28(6):1031-7. Epub 2010 Jan 19. [http://jco.ascopubs.org/content/28/6/1031.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20085941 PubMed]<br />
--><br />
# '''CAN2007:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/4/865.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21562045 PubMed]<br />
## '''Update:''' Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. [http://www.bloodjournal.org/content/124/16/2498 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4199951/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25202139 PubMed]<br />
<br />
==CRd {{#subobject:449fc5|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CRd: '''<u>C</u>'''yclophosphamide, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CLD: '''<u>C</u>'''yclophosphamide, '''<u>L</u>'''enalidomide '''<u>D</u>'''examethasone<br />
<br>RdC: '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone, '''<u>C</u>'''yclophosphamide<br />
===Regimen variant #1 {{#subobject:97779b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ Kumar et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ Palladini et al. 2012 (AC-003-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
**In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
(varies depending on reference)<br />
*Thromboprophylaxis with one of the following:<br />
**Standard patients: [[Aspirin]] 81 to 325 mg PO once per day<br />
**In Kumar et al. 2012, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: [[:Category:Low molecular weight heparins|low molecular weight heparin]] or [[Warfarin (Coumadin)]]<br />
*Kumar et al. 2012: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."<br />
<br />
'''28-day cycle for up to 9 cycles or 2 years, depending on reference'''<br />
<br />
===Regimen variant #2 {{#subobject:ab62e|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/23/5384.long Kastritis et al. 2012]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|ORR: 55% (hematologic response)<br> 22% (organ response)<br />
|-<br />
|}<br />
''This was the highest dose level tested, which had no dose-limiting toxicities.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 100 mg PO once per day on days 1 to 10<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*Proton pump inhibitor<br />
*[[Trimethoprim-Sulfamethoxazole (Bactrim DS)|Trimethoprim-sulfamethoxazole (Bactrim)]], dose and schedule not listed<br />
*[[Valacyclovir (Valtrex)]], dose and schedule not listed<br />
<br />
'''28-day cycle for 12 cycles'''<br />
<br />
===References===<br />
# Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. [http://www.bloodjournal.org/content/119/21/4860.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418771/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22504925 PubMed]<br />
# Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. [http://www.bloodjournal.org/content/119/23/5384.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22517904 PubMed]<br />
# '''AC-003-IT:''' Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. [http://www.haematologica.org/content/98/3/433.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659931/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22983583 PubMed]<br />
<br />
==CTD {{#subobject:8ae28f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
CTD: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br />
===Regimen variant #1 {{#subobject:68db56|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===Regimen variant #2, risk attenuated regimen {{#subobject:79cb8f|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/457.long Wechalekar et al. 2007]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
<br />
''For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.''<br />
====Chemotherapy====<br />
*[[Cyclophosphamide (Cytoxan)]] 500 mg PO once per day on days 1, 8, 15<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Cycle 1: 50 mg PO once per day<br />
**Cycle 2 (if tolerated): 100 mg PO once per day<br />
**Cycle 3 (if tolerated): 150 mg PO once per day<br />
**Cycle 4 onwards (if tolerated): 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
====Supportive medications====<br />
*"Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis<br />
<br />
'''28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response'''<br />
<br />
===References===<br />
# Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. [http://www.bloodjournal.org/content/109/2/457.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16990593 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:866e6e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:21e2c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/7/900.long Kaufman et al. 2017]<br />
| style="background-color:#ffffbe" |Retrospective<br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Daratumumab (Darzalex)]] as follows:<br />
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22<br />
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15<br />
**Cycle 5 onwards: 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Acetaminophen (Tylenol)]] 650 mg PO once, prior to daratumumab<br />
*[[Diphenhydramine (Benadryl)]] 50 mg PO once, prior to daratumumab<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once, prior to daratumumab<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''Retrospective:''' Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. [http://www.bloodjournal.org/content/130/7/900.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28615223 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:6fd012|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:26856d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
''This is the MTD dosing determined in this phase I/II trial.''<br />
====Chemotherapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"''' <br />
====Subsequent treatment====<br />
*Patients with less than PR after four cycles: [[#Ixazomib_.26_Dexamethasone|Ixazomib & dexamethasone]]<br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28550039 PubMed]<br />
<br />
==Ixazomib & Dexamethasone {{#subobject:71db9c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:22a5ec|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/130/5/597.long Sanchorawala et al. 2017]<br />
| style="background-color:#91cf61" |Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Ixazomib_monotherapy|Ixazomib]] x 4, with less than PR<br />
====Chemotherapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycles''' <br />
<br />
===References===<br />
# Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. [http://www.bloodjournal.org/content/130/5/597.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28550039 PubMed]<br />
<br />
==Pd {{#subobject:77727f|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
Pd: '''<u>P</u>'''omalidomide & low-dose '''<u>d</u>'''examethasone<br />
===Regimen variant #1 {{#subobject:e32103|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/129/15/2120.long Palladini et al. 2017 (AC-007-IT)]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2 {{#subobject:5b3fd1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/128/8/1059.long Sanchorawala et al. 2016 (PO-AMYL-PI-0024)]<br />
| style="background-color:#ffffbe" |Phase I/II, <20 pts<br />
|-<br />
|}<br />
''Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:''<br />
====Chemotherapy====<br />
*[[Pomalidomide (Pomalyst)]] 4 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #3 {{#subobject:ef8da|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ Dispenzieri et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Pomalidomide (Pomalyst)]] 2 mg PO once per day<br />
**See Dispenzieri et al. 2012 for dose escalations and reductions<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. [http://www.bloodjournal.org/content/119/23/5397.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369677/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22493299 PubMed]<br />
# '''PO-AMYL-PI-0024:''' Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. [http://www.bloodjournal.org/content/128/8/1059.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27381904 PubMed]<br />
# '''AC-007-IT:''' Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. [http://www.bloodjournal.org/content/129/15/2120.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28130212 PubMed]<br />
<br />
==Rd {{#subobject:50cc20|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
<br>RevDex: '''<u>Rev</u>'''limid (Lenalidomide) & '''<u>Dex</u>'''amethasone<br />
<br>Ld: '''<u>L</u>'''enalidomide & low-dose '''<u>d</u>'''examethasone<br />
<br>LenDex: '''<u>L</u>'''enalidomide & '''<u>D</u>'''examethasone<br />
===Regimen variant #1, weekly dexamethasone {{#subobject:45b0fe|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://link.springer.com/article/10.1007%2Fs00277-011-1244-x Palladini et al. 2012]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day<br />
*[[Omeprazole (Prilosec)]] 20 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Regimen variant #2, pulsed dexamethasone {{#subobject:503e2a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/492.full Sanchorwala et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
**Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 81 or 325 mg PO once per day<br />
*[[:Category:Proton_pump_inhibitors|Proton pump inhibitor]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. [http://www.bloodjournal.org/content/109/2/492.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16960148 PubMed]<br />
# Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. [http://link.springer.com/article/10.1007%2Fs00277-011-1244-x link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21533608 PubMed]<br />
<br />
==RD {{#subobject:34466d|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RD: '''<u>R</u>'''evlimid (Lenalidomide) & high-dose '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:78c466|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/109/2/465.long Dispenzieri et al. 2006]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Treatment failure after [[#Lenalidomide_monotherapy|lenalidomide]] x 3 cycles<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 15 to 18<br />
<br />
'''28-day cycle for 12 or more cycles'''<br />
<br />
===References===<br />
# Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. [http://www.bloodjournal.org/content/109/2/465.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17008538 PubMed]<br />
<br />
[[Category:Light-chain (AL) amyloidosis regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40874Smoldering multiple myeloma2019-11-07T16:24:00Z<p>Samuelrubinstein: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Six cycles of therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
'''42 day cycles, continued until progression'''<br />
<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
||[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40873Smoldering multiple myeloma2019-11-07T16:23:29Z<p>Samuelrubinstein: /* MP {{#subobject:4d7e74|Regimen=2}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Six cycles of therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
'''42 day cycles, continued until progression'''<br />
<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
||[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40872Smoldering multiple myeloma2019-11-07T16:23:13Z<p>Samuelrubinstein: /* Chemotherapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Six cycles of therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
'''42 day cycles, continued until progression'''<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
||[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40871Smoldering multiple myeloma2019-11-07T16:22:57Z<p>Samuelrubinstein: /* MP {{#subobject:4d7e74|Regimen=2}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Six cycles of therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
''42 day cycles, continued until progression''<br />
<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
||[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40870Smoldering multiple myeloma2019-11-07T16:20:23Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Six cycles of therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
''42 day cycles, continued until progression''<br />
<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
||[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40869Smoldering multiple myeloma2019-11-07T16:18:47Z<p>Samuelrubinstein: /* MP {{#subobject:4d7e74|Regimen=2}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Six cycles of therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
''42 day cycles, continued until progression''<br />
<br />
<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40868Smoldering multiple myeloma2019-11-07T16:18:29Z<p>Samuelrubinstein: /* Variant #1: Defined-interval of therapy {{#subobject:f79d0|Variant=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Six cycles of therapy {{#subobject:f79d0|Variant=1}}===<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
''42 day cycles, continued until progression''<br />
<br />
<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40867Smoldering multiple myeloma2019-11-07T16:18:15Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Defined-interval of therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
''42 day cycles, continued until progression''<br />
<br />
<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40866Smoldering multiple myeloma2019-11-07T16:17:30Z<p>Samuelrubinstein: /* MP {{#subobject:4d7e74|Regimen=2}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1: Defined-interval of therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
===Variant #2: Indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x Hjorth et al. 1993]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.25 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
<br />
''42 day cycles, continued until progression''<br />
<br />
<br />
<br />
===References===<br />
# Hjorth M, Hellquist L, Holmberg E, Magnusson B, Rödjer S, Westin J. Initial versus deferred melphalan-prednisone therapy for asymptomatic multiple myeloma stage I--a randomized study. Myeloma Group of Western Sweden. Eur J Haematol. 1993 Feb;50(2):95-102. [https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1600-0609.1993.tb00148.x link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8440364 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40865Smoldering multiple myeloma2019-11-07T16:05:34Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Variant #1 {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
''Note: Patients on the observation arm of this study received this regimen at progression to symptomatic MM''<br />
<br />
<br />
===References===<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40864Smoldering multiple myeloma2019-11-07T15:59:28Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
'''42-day cycles for six cycles'''<br />
<br />
===References===<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40863Smoldering multiple myeloma2019-11-07T15:57:03Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
<br />
'''42-day cycles for six cycles'''<br />
<br />
===References===<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#MP|MP]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40862Smoldering multiple myeloma2019-11-07T15:55:07Z<p>Samuelrubinstein: /* References */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
<br />
'''42-day cycles for six cycles'''<br />
<br />
===References===<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40861Smoldering multiple myeloma2019-11-07T15:54:43Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==MP {{#subobject:4d7e74|Regimen=4}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MP: '''<u>M</u>'''elphalan & '''<u>P</u>'''rednisone<br />
<br />
''Note: This regimen is of historical significance''<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/6691087 Riccardi et al. 2000 (MM87/MM90)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#ffffbf" |Seems not superior<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.21 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 0.5 mg/kg PO once per day on days 1 to 10<br />
<br />
<br />
'''42-day cycles for six cycles'''<br />
<br />
===References===<br />
# '''MM87/MM90:''' Riccardi A, Mora O, Tinelli C, Valentini D, Brugnatelli S, Spanedda R, De Paoli A, Barbarano L, Di Stasi M, Giordano M, Delfini C, Nicoletti G, Bergonzi C, Rinaldi E, Piccinini L, Ascari E. Long-term survival of stage I multiple myeloma <br />
given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study. Cooperative Group of Study and Treatment of Multiple Myeloma. Br J Cancer. 2000 Apr;82(7):1254-60. [Epub ahead of print] [https://www.nature.com/articles/6691087 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10755397 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40858Smoldering multiple myeloma2019-11-07T15:39:34Z<p>Samuelrubinstein: /* References */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40857Smoldering multiple myeloma2019-11-07T15:39:08Z<p>Samuelrubinstein: /* References */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct 15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40856Smoldering multiple myeloma2019-11-07T15:38:24Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|[https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with Barlogie et al. 2008]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
# Barlogie B, van Rhee F, Shaughnessy JD Jr, Epstein J, Yaccoby S, Pineda-Roman M, Hollmig K, Alsayed Y, Hoering A, Szymonifka J, Anaissie E, Petty N, Kumar NS, Srivastava G, Jenkins B, Crowley J, Zeldis JB. Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease. Blood. 2008 Oct<br />
15;112(8):3122-5. doi: 10.1182/blood-2008-06-164228. Epub 2008 Jul 31. [https://ashpublications.org/blood/article/112/8/3122/114933/Seven-year-median-time-to-progression-with] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18669874?report=docsum&format=text PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40855Smoldering multiple myeloma2019-11-07T15:34:06Z<p>Samuelrubinstein: /* Regimen {{#subobject:45c352|Variant=3}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40854Smoldering multiple myeloma2019-11-07T15:33:37Z<p>Samuelrubinstein: /* Thalidomide monotherapy {{#subobject:bec321|Regimen=3}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al. 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al. 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
<br />
'''Continued indefinitely'''<br />
<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40853Smoldering multiple myeloma2019-11-07T15:32:18Z<p>Samuelrubinstein: /* Thalidomide monotherapy {{#subobject:bec321|Regimen=3}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2003.03.139 Weber et al 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 200 -> 800 mg/d, indefinite therapy {{#subobject:f79d0|Variant=3}}===<br />
===Regimen {{#subobject:45c352|Variant=3}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/2402183 Rajkumar et al 2001]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28, then 600 mg PO once per day on days 29 to 42<br />
**Cycle 2 onwards: 800 mg PO once per day<br />
<br />
<br />
'''Continued indefinitely'''<br />
<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
# Rajkumar SV, Dispenzieri A, Fonseca R, Lacy MQ, Geyer S, Lust JA, Kyle RA, Greipp PR, Gertz MA, Witzig TE. Thalidomide for previously untreated indolent or smoldering multiple myeloma. Leukemia. 2001 Aug;15(8):1274-6 [https://www.nature.com/articles/2402183 full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11480571 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40852Smoldering multiple myeloma2019-11-07T15:25:43Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Weber et al 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40851Smoldering multiple myeloma2019-11-07T15:24:51Z<p>Samuelrubinstein: /* Regimen {{#subobject:45c352|Variant=2}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Weber et al 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40850Smoldering multiple myeloma2019-11-07T15:24:10Z<p>Samuelrubinstein: /* Thalidomide monotherapy {{#subobject:bec321|Regimen=3}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Weber et al 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40849Smoldering multiple myeloma2019-11-07T15:23:00Z<p>Samuelrubinstein: /* Thalidomide monotherapy {{#subobject:bec321|Regimen=3}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1, 200 mg/d, indefinite therapy {{#subobject:f79d0|Variant=1}}===<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #2, 200 -> 600 mg/d, indefinite therapy {{#subobject:f79d0|Variant=2}}===<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Weber et al 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40848Smoldering multiple myeloma2019-11-07T15:21:13Z<p>Samuelrubinstein: /* Thalidomide monotherapy {{#subobject:bec321|Regimen=3}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al. 2012 (MC0289)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once every three months<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Regimen {{#subobject:45c352|Variant=2}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Weber et al 2003]<br />
| style="background-color:#91cf60" |Phase II <br />
|-<br />
|}<br />
<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows: <br />
**Cycle 1: Cycle 1: 200 mg PO once per day on days 1 to 7, then 300 mg PO once per day on days 8 to 14, then 400 mg PO once per day on days 15 to 21, then 500 mg PO once per day on days 22 to 29<br />
**Cycle 2 onwards: 600 mg PO once per day<br />
<br />
''Note: The median maximal tolerated dose in this study for patients with smoldering myeloma was 400 mg PO once per day''<br />
<br />
===References===<br />
# '''MC0289:''' Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. [http://jco.ascopubs.org/content/21/1/16.full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12506164 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40846Smoldering multiple myeloma2019-11-07T15:02:41Z<p>Samuelrubinstein: /* All lines of therapy */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:456A52|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: QUIREDEX did not require modern imaging modalities (such as MRI) to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:bec321|Regimen=3}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior TTP<br />
|-<br />
|}<br />
<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[Zoledronic acid (Zometa)]] 4 mg IV once per three months<br />
<br />
''Note: Zoledronic acid was received in both the control and experimental arms.''<br />
<br />
===References===<br />
# Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. doi: 10.1038/leu.2012.236. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013 (QUIREDEX)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[https://www.nature.com/articles/leu2012236 Witzig et al 2012]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
| style="background-color:#fc8d59" |Seems to have inferior TTP<br />
|}<br />
<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# '''QUIREDEX:''' Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
# Witzig TE, Laumann KM, Lacy MQ, Hayman SR, Dispenzieri A, Kumar S, Reeder CB, Roy V, Lust JA, Gertz MA, Greipp PR, Hassoun H, Mandrekar SJ, Rajkumar SV. A phase III randomized trial of thalidomide plus zoledronic acid versus zoledronic acid alone in patients with asymptomatic multiple myeloma. Leukemia. 2013 Jan;27(1):220-5. doi: 10.1038/leu.2012.236. Epub 2012 Aug 20 [https://www.nature.com/articles/leu2012236 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22902362 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40817Smoldering multiple myeloma2019-11-03T15:16:18Z<p>Samuelrubinstein: /* Regimen */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this trial did not require modern imaging modalities to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. doi: 10.1056/NEJMoa1300439. PubMed PMID: 23902483. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. doi: 10.1056/NEJMoa1300439. PubMed PMID: 23902483. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40816Smoldering multiple myeloma2019-11-03T15:15:52Z<p>Samuelrubinstein: /* Regimen {{#subobject:45c352|Variant=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#91cf60" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this trial did not require modern imaging modalities to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. doi: 10.1056/NEJMoa1300439. PubMed PMID: 23902483. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#d73027" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. doi: 10.1056/NEJMoa1300439. PubMed PMID: 23902483. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Smoldering_multiple_myeloma&diff=40815Smoldering multiple myeloma2019-11-03T15:14:22Z<p>Samuelrubinstein: </p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:100%;"<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Page editor'''<br />
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''<br />
|-<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Samuelrubinstein.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Samuelrubinstein|Samuel M. Rubinstein, MD]]<br>Vanderbilt University<br>Nashville, TN</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/rubinstein_md rubinstein_md]<br />
| style="background-color:#F0F0F0; width:15%" |[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
| style="width:35%" |<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
<br />
=All lines of therapy=<br />
<br />
==Lenalidomide monotherapy {{#subobject:bec321|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
<br />
<br />
==Rd {{#subobject:bec321|Regimen=2}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:45c352|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[#Observation|Observation]]<br />
| style="background-color:#1a9850" |Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this trial did not require modern imaging modalities to rule out active myeloma, and therefore it is probable that many patients on this study had active as opposed to smoldering multiple myeloma.''<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 12 to 15<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day<br />
<br />
'''28-day cycle for 9 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. doi: 10.1056/NEJMoa1300439. PubMed PMID: 23902483. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
==Observation==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/JCO.19.01740 Lonial et al. 2019 (ECOG E3A06)]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
| style="background-color:#d73027" |Inferior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 Mateos et al. 2013]<br />
| style="background-color:#1a9851" |Phase III (C)<br />
|[[#Rd|Rd]]<br />
| style="background-color:#d73027" |Seems to have inferior OS<br />
|-<br />
|}<br />
''No treatment.''<br />
<br />
===References===<br />
# '''ECOG E3A06:''' Lonial S, Jacobus S, Fonseca R, Weiss M, Kumar S, Orlowski RZ, Kaufman JL, Yacoub AM, Buadi FK, O'Brien T, Matous JV, Anderson DM, Emmons RV, Mahindra A, Wagner LI, Dhodapkar MV, Rajkumar SV. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 Oct 25:JCO1901740. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.19.01740 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23958922 PubMed]<br />
# Mateos MV, Hernández MT, Giraldo P, de la Rubia J, de Arriba F, López Corral L, Rosiñol L, Paiva B, Palomera L, Bargay J, Oriol A, Prosper F, López J, Olavarría E, Quintana N, García JL, Bladé J, Lahuerta JJ, San Miguel JF. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013 Aug 1;369(5):438-47. doi: 10.1056/NEJMoa1300439. PubMed PMID: 23902483. [https://www.nejm.org/doi/full/10.1056/NEJMoa1300439 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23902483 PubMed]<br />
<br />
[[Category:Smoldering multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinsteinhttps://hemonc.org/w/index.php?title=Multiple_myeloma,_consolidation_and_maintenance&diff=40814Multiple myeloma, consolidation and maintenance2019-11-03T15:03:20Z<p>Samuelrubinstein: /* MPR {{#subobject:611aa1|Regimen=1}} */</p>
<hr />
<div>{| class="wikitable" style="text-align:center; width:50%;"<br />
!colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26"|'''Section editor'''<br />
|-<br />
|style="background-color:#F0F0F0"|[[File:Headshot Cowan.jpg|frameless|upright=0.3|center]]<br />
|<big>[[User:Andrewc072|Andrew J. Cowan, MD]]<br>University of Washington<br>Seattle, WA</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]][https://twitter.com/andrewcowanmd andrewcowanmd]<br>[https://www.linkedin.com/in/andrew-cowan-63b3a130/ LinkedIn]<br />
|-<br />
|}<br />
''Are you looking for a regimen but can't find it here? It is possible that we've moved it to the [[Multiple_myeloma_-_historical|historical regimens page]]. If you still can't find it, please let us know so we can add it!''.<br />
<br><big>'''Note: due to its size/complexity, the multiple myeloma page has been split into three sub-pages:'''<br />
*[[Multiple_myeloma,_induction|Induction (transplant eligible and ineligible)]]<br />
*First-line consolidation and maintenance [''this page'']<br />
*[[Multiple_myeloma,_relapsed/refractory|Relapsed/refractory, including subsequent consolidation and maintenance]]<br />
</big><br />
{| class="wikitable" style="float:right; margin-right: 5px;"<br />
|-<br />
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div><br />
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div><br />
|}<br />
{{TOC limit|limit=3}}<br />
{{#lst:Multiple myeloma|guidelines}}<br />
<section begin=1st-consol /><br />
=Consolidation after first-line therapy=<br />
''Note that there is no crisp distinction between consolidation and maintenance. Generally regimens that are intended for a long or indefinite duration would be considered maintenance, whereas regimens with a short intended course would be considered consolidation.''<br />
<br />
==Bortezomib monotherapy {{#subobject:dd778e|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Variant #1 {{#subobject:66855e|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674665/ Mellqvist et al. 2013 (NMSG 15/05)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Observation|Observation]]<br />
|style="background-color:#d9ef8b"|Might have superior PFS<br />
|-<br />
|}<br />
''This trial only included bortezomib-naive patients; induction regimen was not specified but the majority received Cy-Dex.'' <br />
====Preceding treatment====<br />
*All patients underwent autologous hematopoietic cell transplant at least 3 months prior to starting consolidation.<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Cycles 1 & 2: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11 of a 21-day cycle<br />
**Cycles 3 to 6: 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15 of a 28-day cycle<br />
<br />
====Supportive medications====<br />
*[[:Category:Bisphosphonates|Bisphosphonates]] were administered "according to national guidelines."<br />
<br />
'''22-week course'''<br />
<br />
===Variant #2, 4 out of 5 weeks for 6 months {{#subobject:9a4ece|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/33/33/3921.long Niesvizky et al. 2015 (UPFRONT)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VD|VD]] x 8 versus [[Multiple_myeloma,_induction#VMP|VMP]] x 8 versus [[Multiple_myeloma,_induction#VTD|VTD]] x 8<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
'''35-day cycle for 5 cycles'''<br />
<br />
===Variant #3, 4 out of 6 weeks for 6 months {{#subobject:e72a4c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/119/19/4375.long Kumar et al. 2012 (EVOLUTION)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VDC|VDC]] versus [[Multiple_myeloma,_induction#VDC|VDC-mod]] versus [[Multiple_myeloma,_induction#RVD|VDR]] versus [[Multiple_myeloma,_induction#RVDC|VDCR]]<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 325 mg PO once per day <br />
**[[Warfarin (Coumadin)]] or [[Enoxaparin (Lovenox)]] could be used based on physician discretion<br />
*[[:Category:PCP_prophylaxis|PCP prophylaxis]] recommended<br />
*[[Acyclovir (Zovirax)]] prophylaxis for Herpes zoster recommended<br />
*[[:Category:Bisphosphonates|Bisphosphonates]] could be used "as necessary"<br />
<br />
'''42-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<!-- Presented in abstract form at the 51st American Society of Hematology (ASH) annual meeting, New Orleans, LA, December 7, 2009; the 52nd ASH annual meeting, Orlando, FL, December 6, 2010; and the 13th International Myeloma Workshop, Paris, France, May 5, 2011.--><br />
# '''EVOLUTION:''' Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. [http://www.bloodjournal.org/content/119/19/4375.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22422823 PubMed]<br />
# '''NMSG 15/05:''' Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, Steingrimsdottir H, Abildgaard N, Ahlberg L, Blimark C, Dahl IM, Forsberg K, Gedde-Dahl T, Gregersen H, Gruber A, Guldbrandsen N, Haukås E, Carlson K, Kvam AK, Nahi H, Lindås R, Andersen NF, Turesson I, Waage A, Westin J; Nordic Myeloma Study Group. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood. 2013 Jun 6;121(23):4647-54. Epub 2013 Apr 24. [http://www.bloodjournal.org/content/121/23/4647.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674665/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23616624 PubMed]<br />
<!-- Presented at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, CA, December 10-13, 2011; and the 55th ASH Annual Meeting and Exposition, New Orleans, LA, December 7-10, 2013. --><br />
# '''UPFRONT:''' Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. [http://jco.ascopubs.org/content/33/33/3921.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26056177 PubMed]<br />
<br />
==Bortezomib & Melphalan, then auto HSCT {{#subobject:9c28bc|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Bor-HDM: '''<u>Bor</u>'''tezomib, '''<u>H</u>'''igh '''<u>D</u>'''ose '''<u>M</u>'''elphalan<br />
===Regimen {{#subobject:0bfd33|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/115/1/32.long Roussel et al. 2009]<br />
| style="background-color:#91cf61" |Phase II<br />
|-<br />
|}<br />
{{#lst:Autologous HSCT|0bfd33}}<br />
===References===<br />
# Roussel M, Moreau P, Huynh A, Mary JY, Danho C, Caillot D, Hulin C, Fruchart C, Marit G, Pégourié B, Lenain P, Araujo C, Kolb B, Randriamalala E, Royer B, Stoppa AM, Dib M, Dorvaux V, Garderet L, Mathiot C, Avet-Loiseau H, Harousseau JL, Attal M; Intergroupe Francophone du Myélome (IFM). Bortezomib and high-dose melphalan as conditioning regimen before autologous stem cell transplantation in patients with de novo multiple myeloma: a phase 2 study of the Intergroupe Francophone du Myelome (IFM). Blood. 2010 Jan 7;115(1):32-7. Epub 2009 Nov 2. [http://www.bloodjournal.org/content/115/1/32.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19884643 PubMed]<br />
<br />
==DCEP {{#subobject:431b08|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
DCEP: '''<u>D</u>'''examethasone, '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide, '''<u>P</u>'''latinol (Cisplatin)<br />
<br />
===Regimen {{#subobject:bbd0bf|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/30/4621.long Harousseau et al. 2010 (IFM 2005-01)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|No DCEP<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of CR/nCR rate<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VD|VD]] x 4 versus [[Multiple_myeloma_-_historical#VAD|VAD]] x 4<br />
====Chemotherapy====<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1600 mg/m<sup>2</sup>) <br />
*[[Etoposide (Vepesid)]] 40 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 160 mg/m<sup>2</sup>)<br />
*[[Cisplatin (Platinol)]] 15 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 60 mg/m<sup>2</sup>) <br />
<br />
'''28-day cycle for 2 cycles'''<br />
<br />
====Subsequent treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic cell transplant]]<br />
<br />
===References===<br />
<!-- Presented at the 48th Annual Meeting of the American Society of Hematology (ASH), December 9-12, 2006, Orlando, FL; the 49th Annual Meeting of the ASH, December 8-11, 2007, Atlanta, GA; the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO), May 30-June 3, 2008, Chicago, IL; and the 2008 Annual Meeting of the American Society of Hematology ASH/ASCO Joint Symposium, December 7, 2008, San Francisco, CA. --><br />
# '''IFM 2005-01:''' Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. [http://jco.ascopubs.org/content/28/30/4621.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20823406 PubMed]<br />
<br />
==KTd {{#subobject:bc0c24|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
KTd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>T</u>'''halidomide, '''<u>d</u>'''examethasone<br />
<br />
===Regimen {{#subobject:bc14c4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ Sonneveld et al. 2014]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|high-dose melphalan with stem cell rescue]].''<br />
====Chemotherapy====<br />
*[[Carfilzomib (Kyprolis)]] as follows:<br />
**''Cohort 1:'' 27 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16<br />
**''Cohort 2:'' 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 8, 9, 15, 16<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 4 cycles'''<br />
<br />
===References===<br />
<!-- # '''Abstract:''' Pieter Sonneveld, Emilie Asselberg-Hacker, Sonja Zweegman, Bronno van der Holt, Marie Jose Kersten, Edo Vellenga, Marinus van Marwijk Kooy, Okke de Weerdt, Sarah Lonergan, Antonio Palumbo, Henk Lokhorst. Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network. Blood Nov 2013,122(21)688 [http://www.bloodjournal.org/content/122/21/688 link to abstract] --><br />
# Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. [http://www.bloodjournal.org/content/125/3/449 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25398935 PubMed]<br />
<br />
==Melphalan, then auto HSCT {{#subobject:263542|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Synopsis===<br />
To be completed. This section will give an overview of this commonly used regimen.<br />
===Variant #1, 140 mg/m<sup>2</sup> {{#subobject:255748|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/67/5/1298 Barlogie et al. 1986]<br />
| style="background-color:#ffffbe" |Non-randomized, <20 pts<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 70 mg/m<sup>2</sup> IV once per day on days -2 & -1<br />
<br />
'''Stem cells re-infused on day 0'''<br />
===Variant #2, 200 mg/m<sup>2</sup> {{#subobject:3d1bf6|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/99/3/731.long Moreau et al. 2002 (IFM 9502)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Melphalan_.2B_TBI.2C_then_auto_HSCT|Melphalan & TBI, then auto HSCT]]<br />
|style="background-color:#d9ef8b"|Might have superior OS<br />
|-<br />
|[http://www.bloodjournal.org/content/106/12/3755 Bladé et al. 2005]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#VBMCP.2FVBAD|VBMCP/VBAD]]<br />
|style="background-color:#ffffbf"|Did not meet efficacy endpoint<br />
|-<br />
|[http://jco.ascopubs.org/content/25/17/2434.full Cavo et al. 2007 (Bologna 96)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[Multiple_myeloma_-_historical#Melphalan.2C_then_auto HSCT.2C_then_Melphalan_.26_Busulfan.2C_then_auto HSCT|Melphalan, then auto HSCT, then Melphalan & Busulfan, then auto HSCT]]<br />
|style="background-color:#d73027"|Inferior EFS<br />
|-<br />
|[http://www.bloodjournal.org/content/115/6/1113 Lokhorst et al. 2009 (HOVON-50)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ Morgan et al. 2010 (MRC Myeloma IX)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://ascopubs.org/doi/full/10.1200/jco.2010.32.7312 Björkstrand et al. 2011 (EBMT-NMAM2000)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|MEL200, then auto HSCT, then RIC allo HSCT<br />
| style="background-color:#fc8d59" |Seems to have inferior OS<br />
|-<br />
|[http://www.bloodjournal.org/content/118/22/5752.full Moreau et al. 2011 (IFM 2007-02)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[http://www.bloodjournal.org/content/120/8/1589.long Rosiñol et al. 2012 (GEM05/MENOS65)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (HOVON-65)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ Lok et al. 2014]<br />
|style="background-color:#91cf61"|Non-randomized<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[http://jco.ascopubs.org/content/32/25/2712.full Roussel et al. 2014]<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ Sonneveld et al. 2014]<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html Mai et al. 2015 (GMMG-MM5)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13994/abstract Mai et al. 2016 (GMMG-HD2)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem melphalan, then auto HSCT]]<br />
|style="background-color:#eeee01"|Non-inferior EFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#RVD|RVD consolidation]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|[https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(19)30023-7/fulltext Bashir et al. 2019 (MDACC 2010-0071)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|Bu/Mel, then auto HSCT<br />
| style="background-color:#fc8d59" |Seems to have inferior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
''Treatment preceded by varying induction regimens:''<br />
{| class="wikitable sortable" style="text-align: center"<br />
!'''Trial'''<br />
!'''Induction regimen'''<br />
!'''# of cycles'''<br />
|-<br />
|'''IFM 9502<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|3<br />
|-<br />
|'''Bladé et al. 2005<br />
|[[Multiple_myeloma_-_historical#VBMCP.2FVBAD|VBMCP/VBAD]]<br />
|4<br />
|-<br />
|'''Bologna 96<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|4<br />
|-<br />
|rowspan=2|'''HOVON-50<br />
|[[Multiple_myeloma,_induction#TAD|TAD]]<br />
|3<br />
|-<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|3<br />
|-<br />
|rowspan=2|'''IFM2007-02<br />
|[[Multiple_myeloma,_induction#VTD|vtD]]<br />
|4<br />
|-<br />
|[[Multiple_myeloma,_induction#VD|VD]]<br />
|4<br />
|-<br />
|rowspan=2|'''MRC Myeloma IX<br />
|[[Multiple_myeloma,_induction#CTD|CTD]]<br />
|4 to 6<br />
|-<br />
|[[Multiple_myeloma,_induction#CVAD|CVAD]]<br />
|4 to 6<br />
|-<br />
|rowspan=3|'''GEM05/MENOS65<br />
|[[Multiple_myeloma,_induction#TD|TD]]<br />
|6<br />
|-<br />
|VBMCP/VBAD/B<br />
|6<br />
|-<br />
|[[Multiple_myeloma,_induction#VTD|VTD]]<br />
|6<br />
|-<br />
|rowspan=2|'''HOVON-65<br />
|[[Multiple_myeloma,_induction#PAD|PAD]]<br />
|3<br />
|-<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|3<br />
|-<br />
|'''Lok et al. 2014<br />
|[[Multiple_myeloma,_induction#VTD|vtD]]<br />
|4<br />
|-<br />
|'''Roussel et al. 2014<br />
|[[Multiple_myeloma,_induction#RVD|RVD]]<br />
|3<br />
|-<br />
|'''Sonneveld et al. 2014<br />
|[[Multiple_myeloma,_induction#KTd|KTd]]<br />
|4<br />
|-<br />
|rowspan=2|'''GMMG-MM5<br />
|[[Multiple_myeloma,_induction#VDC|VCD]]<br />
|3<br />
|-<br />
|[[Multiple_myeloma,_induction#PAD|PAd]]<br />
|3<br />
|-<br />
|'''IFM 2009<br />
|[[Multiple_myeloma,_induction#RVD|RVD]]<br />
|3<br />
|-<br />
|}<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day -2<br />
<br />
'''Stem cells re-infused on day 0'''<br />
====Subsequent treatment====<br />
''Treatment followed by varying consolidation and/or maintenance regimens:<br />
{| class="wikitable sortable" style="text-align: center"<br />
!'''Trial'''<br />
!'''Subsequent treatment'''<br />
!'''Type of regimen'''<br />
!'''Duration'''<br />
|-<br />
|'''IFM 9502<br />
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]]<br />
|Maintenance<br />
|1 year<br />
|-<br />
|'''Bladé et al. 2005<br />
|[[Multiple_myeloma_-_historical#Interferon_alfa_.26_Dexamethasone|IFN & Dexamethasone]]<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|'''Bologna 96<br />
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]]<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|rowspan=2|'''HOVON-50<br />
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]] (if induced with VAD)<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|[[#Thalidomide_monotherapy|Thalidomide]] (if induced with TAD)<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|'''IFM2007-02<br />
|Unspecified<br />
|Unspecified<br />
|Unspecified<br />
|-<br />
|rowspan=2|'''MRC Myeloma IX<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|[[Multiple_myeloma_-_historical#Observation|No further treatment]]<br />
|N/A<br />
|N/A<br />
|-<br />
|rowspan=3|'''GEM05/MENOS65<br />
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa-2b]]<br />
|Maintenance<br />
|3 years<br />
|-<br />
|[[#Thalidomide_monotherapy|Thalidomide]] <br />
|Maintenance<br />
|3 years<br />
|-<br />
|[[#VT|TV]]<br />
|Maintenance<br />
|3 years<br />
|-<br />
|rowspan=2|'''HOVON-65<br />
|[[#Bortezomib_monotherapy_2|Bortezomib]] (if induced with PAD)<br />
|Maintenance<br />
|2 years<br />
|-<br />
|[[#Thalidomide_monotherapy|Thalidomide]] (if induced with VAD)<br />
|Maintenance<br />
|2 years<br />
|-<br />
|'''Lok et al. 2014<br />
|[[#VTD|vtD]]<br />
|Consolidation<br />
|2 cycles<br />
|-<br />
|'''Roussel et al. 2014<br />
|[[#RVD|RVD]]<br />
|Consolidation<br />
|2 cycles<br />
|-<br />
|'''Sonneveld et al. 2014<br />
|[[#KTd|KTd]]<br />
|Consolidation<br />
|4 cycles<br />
|-<br />
|rowspan=2|'''GMMG-MM5<br />
|MEL200, then auto HSCT (if at least nCR not achieved)<br />
|Consolidation<br />
|1 cycle<br />
|-<br />
|Lenalidomide<br />
|Consolidation<br />
|Not specified in abstract<br />
|-<br />
|'''IFM 2009<br />
|[[#RVD|RVD]]<br />
|Consolidation<br />
|2 cycles<br />
|-<br />
|}<br />
<br />
===References===<br />
# Barlogie B, Hall R, Zander A, Dicke K, Alexanian R. High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood. 1986 May;67(5):1298-301. [http://www.bloodjournal.org/content/67/5/1298 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/3516252 PubMed]<br />
# '''IFM 9502:''' Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, François S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood. 2002 Feb 1;99(3):731-5. [http://www.bloodjournal.org/content/99/3/731.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11806971 PubMed]<br />
# Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA). High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3755 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16105975 PubMed]<br />
# '''Bologna 96:''' Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. [http://jco.ascopubs.org/content/25/17/2434.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17485707 PubMed]<br />
<!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008. --><br />
# '''HOVON-50:''' Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19880501 PubMed]<br />
## '''Update:''' van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(18)30149-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30290905 PubMed]<br />
# '''MRC Myeloma IX:''' Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62051-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21131037 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. [http://www.bloodjournal.org/content/118/5/1231.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152492/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21652683 PubMed]<br />
## '''Update:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22021371 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. [http://www.haematologica.org/content/97/3/442.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291601/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22058209 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. [http://clincancerres.aacrjournals.org/content/19/21/6030.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23995858 PubMed]<br />
# '''EBMT-NMAM2000:''' Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol. 2011 Aug 1;29(22):3016-22. Epub 2011 Jul 5. Erratum in: J Clin Oncol. 2011 Sep 20;29(27):3721. [https://ascopubs.org/doi/full/10.1200/jco.2010.32.7312 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21730266 PubMed]<br />
## '''Update:''' Gahrton G, Iacobelli S, Björkstrand B, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Carella AM, Beksac M, Bosi A, Milone G, Corradini P, Schönland S, Friberg K, van Biezen A, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Garderet L, Kröger N; EBMT Chronic Malignancies Working Party Plasma Cell Disorders Subcommittee. Autologous/reduced-intensity allogeneic stem cell transplantation vs autologous transplantation in multiple myeloma: long-term results of the EBMT-NMAM2000 study. Blood. 2013 Jun 20;121(25):5055-63. Epub 2013 Mar 12. [http://www.bloodjournal.org/content/121/25/5055.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23482933 PubMed]<br />
# '''IFM 2007-02:''' Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. [http://www.bloodjournal.org/content/118/22/5752.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21849487 PubMed]<br />
# '''GEM05/MENOS65:''' Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. [http://www.bloodjournal.org/content/120/8/1589.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22791289 PubMed]<br />
## '''Update:''' Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. [https://www.nature.com/leu/journal/v31/n9/full/leu201735a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28111466 PubMed]<br />
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]<br />
## '''Subgroup analysis:''' Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. [http://www.bloodjournal.org/content/119/4/940.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22160383 PubMed]<br />
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]<br />
# Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous bortezomib incorporated into the bortezomib-thalidomide-dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. [http://www.haematologica.org/content/99/3/e33.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24532044 PubMed]<br />
# Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. [http://jco.ascopubs.org/content/32/25/2712.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25024076 PubMed]<br />
<!-- # '''Abstract:''' Pieter Sonneveld, Emilie Asselberg-Hacker, Sonja Zweegman, Bronno van der Holt, Marie Jose Kersten, Edo Vellenga, Marinus van Marwijk Kooy, Okke de Weerdt, Sarah Lonergan, Antonio Palumbo, Henk Lokhorst. Dose Escalation Phase 2 Trial Of Carfilzomib Combined With Thalidomide and Low-Dose Dexamethason In Newly Diagnosed, Transplant Eligible Patients With Multiple Myeloma. A Trial Of The European Myeloma Network. Blood Nov 2013,122(21)688 [http://www.bloodjournal.org/content/122/21/688 link to abstract] --><br />
# Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. [http://www.bloodjournal.org/content/125/3/449 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300390/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25398935 PubMed]<br />
# '''GMMG-MM5:''' Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. [https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25787915 PubMed]<br />
# '''GMMG-HD2:''' Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016 Jun;173(5):731-41. Epub 2016 Mar 17. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13994/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26990892 PubMed]<br />
# '''IFM 2009:''' Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28379796 PubMed]<br />
# '''MDACC 2010-0071:''' Bashir Q, Thall PF, Milton DR, Fox PS, Kawedia JD, Kebriaei P, Shah N, Patel K, Andersson BS, Nieto YL, Valdez BC, Parmar S, Rondon G, Delgado R, Hosing C, Popat UR, Oran B, Ciurea SO, Lin P, Weber DM, Thomas SK, Lee HC, Manasanch EE, Orlowski RZ, Williams LA, Champlin RE, Qazilbash MH. Conditioning with busulfan plus melphalan versus melphalan alone before autologous haemopoietic cell transplantation for multiple myeloma: an open-label, randomised, phase 3 trial. Lancet Haematol. 2019 May;6(5):e266-e275. Epub 2019 Mar 22. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(19)30023-7/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30910541 PubMed]<br />
<br />
==MPR {{#subobject:611aa1|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
MPR: '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone, '''<u>R</u>'''evlimid (Lenalidomide)<br />
===Variant #1, 0.18/2/10 {{#subobject:eac77a|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1402888 Palumbo et al. 2014 (MPRvsMEL200)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem Melphalan, then auto HSCT]]<br />
|style="background-color:#fc8d59"|Seems to have inferior OS<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#Rd|Rd induction]] x 4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 0.18 mg/kg PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 2 mg/kg PO once per day on days 1 to 4<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]] versus [[Multiple_myeloma_-_historical#Observation|no further treatment]]<br />
<br />
===Variant #2 {{#subobject:bd5044|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html Falco et al. 2012]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
''Note: this is a component of the sequential "RP-MPR-RP" protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#RP|RP induction]] x 4<br />
====Chemotherapy====<br />
*[[Melphalan (Alkeran)]] 2 mg PO three times per week<br />
*[[Prednisone (Sterapred)]] 50 mg PO three times per week <br />
*[[Lenalidomide (Revlimid)]] 10 or 15 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day, taken during [[Lenalidomide (Revlimid)]] treatment (unclear from protocol if this also means off weeks)<br />
*Antiviral prophylaxis if history of VZV.<br />
<br />
'''28-day cycle for 6 cycles'''<br />
====Subsequent treatment====<br />
*[[#RP_2|RP maintenance]]<br />
<br />
===References===<br />
# Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. [https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22996335 PubMed]<br />
# '''MPRvsMEL200:''' Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. [https://www.nejm.org/doi/full/10.1056/NEJMoa1402888 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184862 PubMed]<br />
<br />
==RP {{#subobject:ceb412|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RP: '''<u>R</u>'''evlimid (Lenalidomide) & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:7d2a7c|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/5/800.long Palumbo et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem MEL-100, then auto HSCT]]<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Prednisone (Sterapred)]] 50 mg PO once every other day<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 100 mg PO once per day during [[Lenalidomide (Revlimid)]] treatment<br />
<br />
'''28-day cycle for 4 cycles'''<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===References===<br />
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. [http://jco.ascopubs.org/content/28/5/800.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048187 PubMed]<br />
## '''Update:''' Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. [http://www.bloodjournal.org/content/122/8/1376.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]<br />
<br />
==RVD {{#subobject:3d2d57|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RVD: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone<br />
<br>VDR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>R</u>'''evlimid (Lenalidomide)<br />
<br>VRD: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>VRd: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
===Variant #1, 2 cycles post-transplant with lower-dose dex {{#subobject:073d3b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===Variant #2, 2 cycles post-transplant with higher-dose dex {{#subobject:073d3b|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/25/2712.full Roussel et al. 2014]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
''Two months after hematologic recovery, patients without progressive disease began treatment.''<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15<br />
<br />
====Supportive medications====<br />
*[[:Category:Low_molecular_weight_heparins |Low–molecular weight heparin (LMWH)]] for DVT prophylaxis<br />
*[[:Category:Antivirals |Antiviral therapy]] with example [[Valacyclovir (Valtrex) | valacyclovir]] given, for herpes zoster prevention<br />
*[[:Category:Antibacterials |Antibiotic prophylaxis]] with example [[Amoxicillin | amoxicillin]] given, for bacterial infections <br />
<br />
'''21-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===Variant #3, 5 cycles, no transplant {{#subobject:073d3b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Melphalan.2C_then_auto_HSCT|Melphalan, then auto HSCT]]<br />
|style="background-color:#d73027"|Inferior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#RVD|RVD induction]] x 3<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12<br />
<br />
'''21-day cycle for 5 cycles'''<br />
====Subsequent treatment====<br />
*[[#Lenalidomide_monotherapy|Lenalidomide maintenance]]<br />
<br />
===Variant #4, 8 cycles, no transplant {{#subobject:7fe92b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030380/ Jacobus et al. 2016 (E1A05)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|Rd<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
''Note: this trial closed early due to poor accrual so only descriptive results are available.''<br />
====Preceding treatment====<br />
*Dexamethasone-based induction for 1 to 6 cycles<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15<br />
<br />
'''21-day cycle for 8 cycles'''<br />
===References===<br />
# '''Retrospective:''' Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar;28(3):690-3. Epub 2013 Nov 13. [https://www.nature.com/leu/journal/v28/n3/full/leu2013335a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24220275 PubMed]<br />
# Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. [http://jco.ascopubs.org/content/32/25/2712.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25024076 PubMed]<br />
# '''E1A05:''' Jacobus SJ, Rajkumar SV, Weiss M, Stewart AK, Stadtmauer EA, Callander NS, Dreosti LM, Lacy MQ, Fonseca R. Randomized phase III trial of consolidation therapy with bortezomib-lenalidomide-Dexamethasone (VRd) vs bortezomib-dexamethasone (Vd) for patients with multiple myeloma who have completed a dexamethasone based induction regimen. Blood Cancer J. 2016 Jul 29;6(7):e448. [https://www.nature.com/articles/bcj201655 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5030380/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27471864 PubMed] <br />
# '''IFM 2009:''' Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28379796 PubMed]<br />
<br />
==Tandem melphalan, then auto HSCT {{#subobject:dd75e9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, MEL100 x 2 {{#subobject:b2cefd|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/5/800.long Palumbo et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
|VGPR or better: 82%<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#PAD_doxil|PAD doxil induction]] x 4<br />
====Chemotherapy, first transplant====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
====Chemotherapy, second transplant====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once (day not specified)<br />
====Subsequent treatment====<br />
*[[#RP_2|RP maintenance]]<br />
<br />
===Variant #2, MEL140, then MEL200 {{#subobject:509dbc|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/108/10/3289.long Attal et al. 2006 (IFM 99-02)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma_-_historical#VAD|VAD]] x 3 to 4<br />
====Chemotherapy, first transplant====<br />
*[[Melphalan (Alkeran)]] 140 mg/m<sup>2</sup> IV once (day not specified)<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
====Chemotherapy, second transplant====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once (day not specified)<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma_-_historical#Observation|Observation]] versus [[#Thalidomide_monotherapy|thalidomide maintenance]]<br />
<br />
===Variant #3, MEL200 x 2 {{#subobject:dd954b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/115/6/1113 Lokhorst et al. 2009 (HOVON-50)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[http://www.bloodjournal.org/content/115/10/1873.long Palumbo et al. 2009 (GIS MM2001)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|MEL100 x 2<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3611089/ Krishnan et al. 2011 (BMT CTN 0102)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Melphalan.2C_then_auto HSCT.2C_then_RIC_allo HSCT|MEL200, then auto HSCT, then RIC allo HSCT]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS36<br />
|-<br />
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (GMMG-HD4)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1402888 Palumbo et al. 2014 (MPRvsMEL200)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#MPR|MPR consolidation]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract Gay et al. 2015 (EMN-441)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|CRD consolidation<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.13994/abstract Mai et al. 2016 (GMMG-HD2)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#Melphalan.2C_then_auto_HSCT|Melphalan, then auto HSCT]]<br />
|style="background-color:#eeee01"|Non-inferior EFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
{| class="wikitable sortable" style="text-align: center"<br />
!'''Trial'''<br />
!'''Induction regimen'''<br />
!'''# of cycles'''<br />
|-<br />
|rowspan=2|'''HOVON-50<br />
|[[Multiple_myeloma,_induction#TAD|TAD]]<br />
|3<br />
|-<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|3<br />
|-<br />
|'''BMT CTN 0102<br />
|Not specified<br />
|N/A<br />
|-<br />
|rowspan=2|'''GMMG-HD4<br />
|[[Multiple_myeloma,_induction#PAD|PAD]]<br />
|3<br />
|-<br />
|[[Multiple_myeloma_-_historical#VAD|VAD]]<br />
|3<br />
|-<br />
|'''MPRvsMEL200<br />
|[[Multiple_myeloma,_induction#Rd|Rd]]<br />
|4<br />
|-<br />
|'''EMN-441<br />
|[[Multiple_myeloma,_induction#Rd|Rd]]<br />
|4<br />
|-<br />
|}<br />
====Chemotherapy, first transplant====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day -2<br />
<br />
'''Stem cells re-infused on day 0'''<br />
<br />
====Chemotherapy, second transplant====<br />
*[[Melphalan (Alkeran)]] 200 mg/m<sup>2</sup> IV once on day -2<br />
<br />
'''Stem cells re-infused on day 0'''<br />
====Subsequent treatment====<br />
''Treatment followed by varying consolidation and/or maintenance regimens:<br />
{| class="wikitable sortable" style="text-align: center"<br />
!'''Trial'''<br />
!'''Subsequent regimen'''<br />
!'''Type of regimen'''<br />
!'''Duration'''<br />
|-<br />
|rowspan=2|'''HOVON-50<br />
|[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa]] (if induced with VAD)<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|[[#Thalidomide_monotherapy|Thalidomide]] (if induced with TAD)<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|rowspan=2|'''BMT CTN 0102<br />
|[[Multiple_myeloma_-_historical#Observation|No further treatment]]<br />
|N/A<br />
|N/A<br />
|-<br />
|[[#TD_2|Thal-Dex]]<br />
|Maintenance<br />
|1 year<br />
|-<br />
|rowspan=2|'''HOVON-65<br />
|[[#Bortezomib_monotherapy_2|Bortezomib]] (if induced with PAD)<br />
|Maintenance<br />
|2 years<br />
|-<br />
|[[#Thalidomide_monotherapy|Thalidomide]] (if induced with VAD)<br />
|Maintenance<br />
|2 years<br />
|-<br />
|rowspan=2|'''MPRvsMEL200<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|[[Multiple_myeloma_-_historical#Observation|No further treatment]]<br />
|N/A<br />
|N/A<br />
|-<br />
|rowspan=2|'''EMN-441<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|[[#RP_2|RP]]<br />
|Maintenance<br />
|Indefinite<br />
|-<br />
|}<br />
<br />
===Variant #4, MEL200 x 2 (split doses) {{#subobject:9ceef8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/89/3/789.long Barlogie et al. 1997 (Total Therapy 1)]<br />
|style="background-color:#91cf61"|Non-randomized<br />
|style="background-color:#d3d3d3"|<br />
|83%<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa065464 Bruno et al. 2007]<br />
|style="background-color:#1a9851"|Randomized (C)<br />
|TBI, then allo HSCT<br />
| style="background-color:#d73027" |Inferior OS<br />
|-<br />
|}<br />
''Note: reported efficacy for Total Therapy 1 is based on the 1999 update. Bruno et al. 2007 does not contain treatment details.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma_-_historical#EDAP|EDAP]] x 1<br />
====Chemotherapy, first transplant====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -3 & -2<br />
<br />
====Immunotherapy====<br />
*[[Allogeneic stem cells]]<br />
'''Stem cells transfused on day 0'''<br />
<br />
====Chemotherapy, second transplant====<br />
*[[Melphalan (Alkeran)]] 100 mg/m<sup>2</sup> IV once per day on days -3 & -2<br />
<br />
====Immunotherapy====<br />
*[[Allogeneic stem cells]]<br />
'''Stem cells transfused on day 0'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|Interferon alfa maintenance]]<br />
<br />
===References===<br />
# '''Total Therapy 1:''' Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. [http://www.bloodjournal.org/content/89/3/789.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9028309 PubMed]<br />
## '''Update:''' Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. [http://www.bloodjournal.org/content/93/1/55.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9864146 PubMed]<br />
## '''Pooled update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]<br />
# '''IFM 99-02:''' Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. [http://www.bloodjournal.org/content/108/10/3289.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16873668 PubMed]<br />
## '''Update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]<br />
# Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omedè P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa065464 link to original article] '''does not contain protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17360989 PubMed]<br />
<!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008. --><br />
# '''HOVON-50:''' Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19880501 PubMed]<br />
## '''Update:''' van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(18)30149-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30290905 PubMed]<br />
# '''GIS MM2001:''' Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M, Ria R, Pisani F, Cangialosi C, Caravita T, Levi A, Meloni G, Nozza A, Pregno P, Gabbas A, Callea V, Rizzo M, Annino L, De Stefano V, Musto P, Baldi I, Cavallo F, Petrucci MT, Massaia M, Boccadoro M. Melphalan 200 mg/m(2) versus melphalan 100 mg/m(2) in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Blood. 2010 Mar 11;115(10):1873-9. Epub 2009 Dec 1. Erratum in: Blood. 2010 Sep 23;116(12):2195. [http://www.bloodjournal.org/content/115/10/1873.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19965659 PubMed]<br />
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. [http://jco.ascopubs.org/content/28/5/800.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048187 PubMed]<br />
## '''Update:''' Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. [http://www.bloodjournal.org/content/122/8/1376.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]<br />
# '''GIMEMA MM-BO2005:''' Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61424-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21146205 PubMed]<br />
## '''Update:''' Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. [http://www.bloodjournal.org/content/120/1/9.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22498745 PubMed]<br />
# Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. Epub 2011 Sep 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3611089/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21962393 PubMed]<br />
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]<br />
## '''Subgroup analysis:''' Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. [http://www.bloodjournal.org/content/119/4/940.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22160383 PubMed]<br />
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]<br />
# '''Meta-analysis:''' Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant. 2013 Apr;48(4):562-7. Epub 2012 Sep 10. Review. [https://www.nature.com/bmt/journal/v48/n4/full/bmt2012173a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22964593 PubMed]<br />
# '''MPRvsMEL200:''' Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. [https://www.nejm.org/doi/full/10.1056/NEJMoa1402888 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184862 PubMed]<br />
# '''EMN-441:''' Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26596670 PubMed]<br />
# '''GMMG-HD2:''' Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016 Jun;173(5):731-41. Epub 2016 Mar 17. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.13994/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26990892 PubMed]<br />
<br />
==TD {{#subobject:13b509|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
TD: '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br>Thal-Dex: '''<u>Thal</u>'''idomide, '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:f79d0|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61424-9/fulltext Cavo et al. 2010 (GIMEMA MM-BO2005)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem MEL200 with auto HSCT]], with interim Thal-Dex maintenance (see paper for details)<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 20 to 23<br />
<br />
====Supportive medications====<br />
*[[Acyclovir (Zovirax)]] prophylaxis recommended<br />
<br />
'''35-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_2|Dexamethasone maintenance]]<br />
===References===<br />
# '''GIMEMA MM-BO2005:''' Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61424-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21146205 PubMed]<br />
## '''Update:''' Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. [http://www.bloodjournal.org/content/120/1/9.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22498745 PubMed]<br />
<br />
==VMP {{#subobject:028a65|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VMP: '''<u>V</u>'''elcade (Bortezomib), '''<u>M</u>'''elphalan, '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:a9c980|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/108/7/2165.long Mateos et al. 2006]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
''Note: this was the phase II portion of this phase I/II study.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VMP|VMP induction]]<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Melphalan (Alkeran)]] 9 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 4<br />
<br />
'''35-day cycle for 5 cycles'''<br />
===References===<br />
# Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006 Oct 1;108(7):2165-72. Epub 2006 Jun 13. [http://www.bloodjournal.org/content/108/7/2165.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16772605 PubMed] <br />
<br />
==VTD {{#subobject:c74cc6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VTD: '''<u>V</u>'''elcade (Bortezomib), '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
===Variant #1, "vTD" {{#subobject:ac81d8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ Lok et al. 2014]<br />
|style="background-color:#91cf61"|Non-randomized<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|Melphalan with autologous hematopoietic stem cell transplantation]]<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1 mg/m<sup>2</sup> SC once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
*[[Dexamethasone (Decadron)]] 40 mg (route not specified) once per day on days 1 to 4<br />
<br />
'''21-day cycle for 2 cycles'''<br />
<br />
===Variant #2 {{#subobject:85c53d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961424-9/fulltext Cavo et al. 2010 (GIMEMA MM-BO2005)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
''VTD consolidation is to begin 3 months after the second transplant.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VTD|VTD induction]], then [[#Melphalan.2C_then_auto_HSCT|high-dose melphalam with tandem autologous hematopoietic stem cell transplant]]<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day on days 1 to 35<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23<br />
<br />
====Supportive medications====<br />
*[[Acyclovir (Zovirax)]] prophylaxis recommended<br />
<br />
'''35-day cycle for 2 cycles'''<br />
====Subsequent treatment====<br />
*[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_2|Dexamethasone maintenance]]<br />
<br />
===Variant #3 {{#subobject:9a493a|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/12/2077.long Ladetto et al. 2010 (GIMEMA VEL-03-096)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|Melphalan, then HSCT]], with at least a very good partial response (VGPR)<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.6 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day, increased by 50 mg each week, up to a maximum of 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18<br />
<br />
'''35-day cycle for 4 cycles'''<br />
<br />
===References===<br />
# '''GIMEMA VEL-03-096:''' Ladetto M, Pagliano G, Ferrero S, Cavallo F, Drandi D, Santo L, Crippa C, De Rosa L, Pregno P, Grasso M, Liberati AM, Caravita T, Pisani F, Guglielmelli T, Callea V, Musto P, Cangialosi C, Passera R, Boccadoro M, Palumbo A. Major tumor shrinking and persistent molecular remissions after consolidation with bortezomib, thalidomide, and dexamethasone in patients with autografted myeloma. J Clin Oncol. 2010 Apr 20;28(12):2077-84. Epub 2010 Mar 22. [http://jco.ascopubs.org/content/28/12/2077.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20308672 PubMed]<br />
## '''Update:''' Ferrero S, Ladetto M, Drandi D, Cavallo F, Genuardi E, Urbano M, Caltagirone S, Grasso M, Rossini F, Guglielmelli T, Cangialosi C, Liberati AM, Callea V, Carovita T, Crippa C, De Rosa L, Pisani F, Falcone AP, Pregno P, Oliva S, Terragna C, Musto P, Passera R, Boccadoro M, Palumbo A. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. Leukemia. 2015 Mar;29(3):689-95. Epub 2014 Jul 16. [https://www.nature.com/leu/journal/v29/n3/full/leu2014219a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25027515 PubMed]<br />
# '''GIMEMA MM-BO2005:''' Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2961424-9/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21146205 PubMed]<br />
## '''Update:''' Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. [http://www.bloodjournal.org/content/120/1/9.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22498745 PubMed]<br />
# Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous bortezomib incorporated into the bortezomib-thalidomide-dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. [http://www.haematologica.org/content/99/3/e33.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3943328/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24532044 PubMed]<br />
<br />
=Maintenance after first-line therapy=<br />
''Note that there is no crisp distinction between consolidation and maintenance. Generally regimens that are intended for a long or indefinite duration would be considered maintenance, whereas regimens with a short intended course would be considered consolidation.''<br />
<br />
==Bortezomib monotherapy {{#subobject:d759b6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, IV x 2 years {{#subobject:85e781|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (HOVON-65)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
|style="background-color:#1a9850"|Superior PFS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (GMMG-HD4)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
|style="background-color:#1a9850"|Superior PFS (*)<br />
|-<br />
|}<br />
''Note that in the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint.''<br />
====Preceding treatment====<br />
*HOVON-65: [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with single autologous hematopoietic stem cell transplant]]<br />
*GMMG-HD4: [[#Tandem_melphalan.2C_then_auto_HSCT|High-dose melphalan with tandem autologous hematopoietic stem cell transplants]]<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once on day 1<br />
<br />
'''14-day cycle for 52 cycles (2 years)'''<br />
<br />
===Variant #2, SC, indefinite {{#subobject:3897c8|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v30/n6/full/leu201636a.html Larocca et al. 2016]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VP|VP]] x 9<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> SC once on day 1<br />
<br />
'''14-day cycles'''<br />
===References===<br />
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]<br />
## '''Subgroup analysis:''' Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. [http://www.bloodjournal.org/content/119/4/940.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22160383 PubMed]<br />
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]<br />
# Larocca A, Bringhen S, Petrucci MT, Oliva S, Falcone AP, Caravita T, Villani O, Benevolo G, Liberati AM, Morabito F, Montefusco V, Passera R, De Rosa L, Omedé P, Vincelli ID, Spada S, Carella AM, Ponticelli E, Derudas D, Genuardi M, Guglielmelli T, Nozzoli C, Aghemo E, De Paoli L, Conticello C, Musolino C, Offidani M, Boccadoro M, Sonneveld P, Palumbo A. A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma. Leukemia. 2016 Jun;30(6):1320-6. [https://www.nature.com/leu/journal/v30/n6/full/leu201636a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26898189 PubMed]<br />
<br />
==Carfilzomib monotherapy {{#subobject:cf0af4|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, bi-weekly {{#subobject:fdc86d|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://www.bloodjournal.org/content/124/1/63 Bringhen et al. 2014 (IST-CAR-506)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#KCd|CCyd]] x 9<br />
====Chemotherapy====<br />
*[[Carfilzomib (Kyprolis)]] 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 15, 16<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, weekly {{#subobject:54dd57|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/articles/leu2017327 Bringhen et al. 2017 (IST-CAR-561)]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
''Note: this is the MTD established for the phase II portion of the trial.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#KCd|wKCyd]] x 9<br />
====Chemotherapy====<br />
*[[Carfilzomib (Kyprolis)]] 70 mg/m<sup>2</sup> IV once per day on days 1, 8, 15<br />
<br />
'''28-day cycles'''<br />
===References===<br />
<!-- # '''Abstract:''' Palumbo, Antonio; Bringhen, Sara; Villani, Oreste; Siniscalchi, Agostina; Russo, Eleonora; Uccello, Giuseppina; Cerrato, Chiara; Gilestro, Milena; Rossi, Davide; Boccadoro, Mario. Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients. ASH Annual Meeting Abstracts 2012 120: 730 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/730 link to abstract] --><br />
# '''IST-CAR-506:''' Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. [http://www.bloodjournal.org/content/124/1/63 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24855212 PubMed]<br />
# '''IST-CAR-561:''' Bringhen S, D'Agostino M, De Paoli L, Montefusco V, Liberati AM, Galieni P, Grammatico S, Muccio VE, Esma F, De Angelis C, Musto P, Ballanti S, Offidani M, Petrucci MT, Gaidano G, Corradini P, Palumbo A, Sonneveld P, Boccadoro M. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018 Apr;32(4):979-985. Epub 2017 Nov 16. [https://www.nature.com/articles/leu2017327 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29263440 PubMed]<br />
<br />
==Daratumumab monotherapy {{#subobject:744fd9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:9dcf90|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1714678 Mateos et al. 2017 (ALCYONE)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#Dara-VMP|Dara-VMP]] x 9<br />
====Chemotherapy====<br />
*[[Daratumumab (Darzalex)]] 16 mg/kg IV once on day 1<br />
<br />
====Supportive medications====<br />
*[[Dexamethasone (Decadron)]] 20 mg IV or PO once on day 1, prior to [[Daratumumab (Darzalex)]]<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# '''ALCYONE:''' Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1714678 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/29231133 PubMed]<br />
<br />
==Ixazomib monotherapy {{#subobject:af8692|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, indefinite {{#subobject:214582|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71125-8/abstract Kumar et al. 2014 (C16005)]<br />
|style="background-color:#91cf61"|Phase I/II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#IRd|IRd]] x 12<br />
====Chemotherapy====<br />
*[[Ixazomib (Ninlaro)]] 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycles''' <br />
<br />
===Variant #2, 2-year course {{#subobject:532db5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)33003-4/fulltext Dimopoulos et al. 2018 (TOURMALINE-MM3)]<br />
| style="background-color:#1a9851" |Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Placebo|Placebo]]<br />
| style="background-color:#1a9850" |Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|Melphalan with auto HSCT]]<br />
====Chemotherapy====<br />
*[[Ixazomib (Ninlaro)]] as follows:<br />
**Cycles 1 to 4: 3 mg PO once per day on days 1, 8, 15<br />
**Cycle 5 onwards, if tolerated: 4 mg PO once per day on days 1, 8, 15<br />
<br />
'''28-day cycle for up to 26 cycles (2 years)'''<br />
<br />
===References===<br />
<!-- Presented at ASH 2012 and ASH 2014, Abstract 82: Long-Term Ixazomib Maintenance Is Tolerable and Improves Depth of Response Following Ixazomib-Lenalidomide-Dexamethasone Induction in Patients (Pts) with Previously Untreated Multiple Myeloma (MM): Phase 2 Study Results --><br />
# '''C16005:''' Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)71125-8/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25456369 PubMed]<br />
## '''Update:''' Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Rajkumar SV, Richardson PG. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance. Leukemia. 2019 Jul;33(7):1736-1746. Epub 2019 Jan 29. [https://www.nature.com/articles/s41375-019-0384-1 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30696949 PubMed]<br />
# '''TOURMALINE-MM3:''' Dimopoulos MA, Gay F, Schjesvold F, Beksac M, Hajek R, Weisel KC, Goldschmidt H, Maisnar V, Moreau P, Min CK, Pluta A, Chng WJ, Kaiser M, Zweegman S, Mateos MV, Spencer A, Iida S, Morgan G, Suryanarayan K, Teng Z, Skacel T, Palumbo A, Dash AB, Gupta N, Labotka R, Rajkumar SV; TOURMALINE-MM3 study group. Oral ixazomib maintenance following autologous stem cell transplantation (TOURMALINE-MM3): a double-blind, randomised, placebo-controlled phase 3 trial. Lancet. 2019 Jan 19;393(10168):253-264. Epub 2018 Dec 10. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)33003-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/30545780 PubMed]<br />
<br />
==KRd {{#subobject:9f1904|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
KRd: '''<u>K</u>'''yprolis (Carfilzomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
<br>CRd: '''<u>C</u>'''arfilzomib, '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:df3763|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ Jakubowiak et al. 2012 (UMCC 2009.056)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
''This is the MTD dosing in this phase I/II trial.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#KRd|KRd]] x 8<br />
====Chemotherapy====<br />
*[[Carfilzomib (Kyprolis)]] 36 mg/m<sup>2</sup> IV once per day on days 1, 2, 15, 16<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 20 mg (route not specified) once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycle for 16 cycles'''<br />
====Subsequent treatment====<br />
*It was recommended that patients proceed to [[#Lenalidomide_monotherapy|lenalidomide maintenance]]<br />
<br />
===References===<br />
# '''UMCC 2009.056:''' Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. [http://www.bloodjournal.org/content/120/9/1801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22665938 PubMed]<br />
<br />
==Lenalidomide monotherapy {{#subobject:1bb17c|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, indefinite 10 mg 21/28 {{#subobject:7a71f8|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/25/28/4459.long Palumbo et al. 2007a]<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[http://jco.ascopubs.org/content/28/5/800.long Palumbo et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1112704 Palumbo et al. 2012 (MM-015)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Placebo|Placebo]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1402888 Palumbo et al. 2014 (MPRvsMEL200)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Observation|Observation]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ Stewart et al. 2015 (ECOG E1A06)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract Gay et al. 2015 (EMN-441)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#RP_2|RP]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#RP_2|RP]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|[http://www.bloodjournal.org/content/127/9/1109.long Zweegman et al. 2016 (HOVON87/NMSG18)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#Thalidomide_monotherapy|Thalidomide]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318225/ Jackson et al. 2018 (UK NCRI Myeloma XI)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Observation|Observation]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Palumbo et al. 2007a & MM-015: [[Multiple_myeloma,_induction#MPR|MPR induction]] x 9<br />
*Palumbo et al. 2010: [[#RP|RP consolidation]] <br />
*MPRvsMEL200: [[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic stem cell transplants]] versus [[#MPR|MPR consolidation]]<br />
*ECOG E1A06: [[Multiple_myeloma,_induction#MPR|mPR induction]] x 12<br />
*EMN-441: [[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic cell transplants]] versus CRD consolidation<br />
*EMN01: [[Multiple_myeloma,_induction#CPR|CPR]] versus [[Multiple_myeloma,_induction#MPR|MPR]] versus [[Multiple_myeloma,_induction#Rd|Rd]] induction x 9<br />
*HOVON87/NMSG18: [[Multiple_myeloma,_induction#MPR|MPR induction]] x 9<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
<br />
====Supportive medications====<br />
*Varies depending on reference:<br />
*'''MM-015:''' [[Aspirin]] 75 to 100 mg PO once per day<br />
*'''Palumbo et al. 2007a and Palumbo et al. 2010:''' [[Aspirin]] 100 mg PO once per day<br />
*'''ECOG E1A06:''' [[Aspirin]] was required (dose not specified)<br />
**''Full anticoagulation was used for patients at "higher risk" for DVT''<br />
*'''EMN01:''' [[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)<br />
*'''ECOG E1A06:''' [[Pamidronate (Aredia)]] 90 mg IV once per month recommended for patients with "active bone disease"<br />
*'''Palumbo et al. 2007a:''' [[Ciprofloxacin (Cipro)]] 500 mg PO twice per day<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, indefinite 15 mg per day {{#subobject:afeaa0|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1114138 Attal et al. 2012 (IFM 2005-02)]<br />
|style="background-color:#1a9851"|Phase III (E-RT)<br />
|[[Multiple_myeloma_-_historical#Placebo|Placebo]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|}<br />
''Note: this is "Maintenance Study 2" listed in the package insert.''<br />
====Chemotherapy, consolidation====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycle for 2 cycles, then'''<br />
<br />
====Chemotherapy, maintenance====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day x 3 months, then increased to 15 mg PO once per day if tolerated<br />
<br />
====Supportive medications====<br />
*"Thromboprophylaxis was not used"<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, indefinite 30 mg per day {{#subobject:9d6a85|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744390/ McCarthy et al. 2012 (CALGB 100104)]<br />
|style="background-color:#1a9851"|Phase III (E-RT)<br />
|[[Multiple_myeloma_-_historical#Placebo|Placebo]]<br />
|style="background-color:#91cf60"|Seems to have superior OS<br />
|-<br />
|}<br />
''Note: this is "Maintenance Study 1" listed in the package insert.''<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|Melphalan with auto HSCT]], within 100 to 120 days<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 20 mg PO once per day; after 3 months, dose may be increased to 30 mg PO once per day if the patient's ANC remains at least 1000/uL and platelet count is at least 75 x 10<sup>9</sup>/L<br />
**Dose adjustments can be found in the paper's supplementary appendix<br />
<br />
====Supportive medications====<br />
*Patients at high risk of deep venous thrombosis (DVT) or pulmonary embolism (PE) received [[Aspirin]], [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]], or [[Warfarin (Coumadin)]] unless contraindicated. High risk patients were defined as people with: history of diabetes, coronary artery disease, "DVT/PE, significant family history, performance status of at least 2, smoking history, use of oral contraceptives, and[/or] concurrent use of epoetin."<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #4, 2 years of 25 mg 21/28 {{#subobject:537dbc|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://oncology.jamanetwork.com/article.aspx?articleid=2363017 Korde et al. 2016 (NCI 12-C-0107)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|[http://oncology.jamanetwork.com/article.aspx?articleid=2363017 Korde et al. 2016 (NCI 11-C-0221)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#KRd|KRd]] x 8<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycle for up to 24 cycles'''<br />
<br />
===Variant #5, 1 year of 10 to 15 mg per day {{#subobject:99cf02|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/32/25/2712.full Roussel et al. 2014]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|[https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 Attal et al. 2017 (IFM 2009)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#RVD|RVD consolidation]]<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day, escalated to 15 mg PO once per day after 3 months, if tolerated.<br />
<br />
'''12-month course'''<br />
<br />
===Variant #6, indefinite 25 mg 21/28 {{#subobject:2650d7|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ Jakubowiak et al. 2012 (UMCC 2009.056)]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#KRd|KRd]] x 24<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007 Oct 1;25(28):4459-65. Epub 2007 Sep 4. [http://jco.ascopubs.org/content/25/28/4459.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17785703 PubMed]<br />
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. [http://jco.ascopubs.org/content/28/5/800.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20048187 PubMed]<br />
## '''Update:''' Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. [http://www.bloodjournal.org/content/122/8/1376.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23775712 PubMed]<br />
# '''CALGB 100104:''' McCarthy PL, Owzar K, Hofmeister CC, Hurd DD, Hassoun H, Richardson PG, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, Van Besien K, Gentile T, Isola L, Maziarz RT, Gabriel DA, Bashey A, Landau H, Martin T, Qazilbash MH, Levitan D, McClune B, Schlossman R, Hars V, Postiglione J, Jiang C, Bennett E, Barry S, Bressler L, Kelly M, Seiler M, Rosenbaum C, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Anderson KC, Linker C. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-81. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114083 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1114083/suppl_file/nejmoa1114083_appendix.pdf link to supplementary appendix] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744390/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22571201 PubMed]<br />
## '''Update:''' Holstein SA, Jung SH, Richardson PG, Hofmeister CC, Hurd DD, Hassoun H, Giralt S, Stadtmauer EA, Weisdorf DJ, Vij R, Moreb JS, Callander NS, van Besien K, Gentile TG, Isola L, Maziarz RT, Bashey A, Landau H, Martin T, Qazilbash MH, Rodriguez C, McClune B, Schlossman RL, Smith SE, Hars V, Owzar K, Jiang C, Boyd M, Schultz C, Wilson M, Hari P, Pasquini MC, Horowitz MM, Shea TC, Devine SM, Linker C, Anderson KC, McCarthy PL. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017 Sep;4(9):e431-e442. Epub 2017 Aug 17. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30140-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28826616 PubMed]<br />
# '''IFM2005-02:''' Attal M, Lauwers-Cances V, Marit G, Caillot D, Moreau P, Facon T, Stoppa AM, Hulin C, Benboubker L, Garderet L, Decaux O, Leyvraz S, Vekemans MC, Voillat L, Michallet M, Pegourie B, Dumontet C, Roussel M, Leleu X, Mathiot C, Payen C, Avet-Loiseau H, Harousseau JL; IFM Investigators. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1782-91. [https://www.nejm.org/doi/full/10.1056/NEJMoa1114138 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22571202 PubMed]<br />
## '''Update: Abstract:''' Michel Attal, MD, Valerie Cances Lauwers, Gerald Marit, Denis Caillot, Thierry Facon, MD, Cyrille Hulin, Philippe Moreau, MD, Claire Mathiot, Murielle Roussel, Catherine Payen, H. Avet-Loiseau and Jean Luc Harousseau. Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA : Final Analysis of the IFM 2005-02. ASH 2010 Abstract 310. [https://ash.confex.com/ash/2010/webprogram/Paper26522.html link to abstract]<br />
# '''UMCC 2009.056:''' Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. [http://www.bloodjournal.org/content/120/9/1801.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5162553/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22665938 PubMed]<br />
# '''MM-015:''' Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. [https://www.nejm.org/doi/full/10.1056/NEJMoa1112704 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22571200 PubMed]<br />
# Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. [http://jco.ascopubs.org/content/32/25/2712.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25024076 PubMed]<br />
# '''MPRvsMEL200:''' Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. [https://www.nejm.org/doi/full/10.1056/NEJMoa1402888 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25184862 PubMed]<br />
# '''GMMG-MM5:''' Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. [https://www.nature.com/leu/journal/v29/n8/full/leu201580a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25787915 PubMed]<br />
# '''ECOG E1A06:''' Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. [http://www.bloodjournal.org/content/126/11/1294.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26157076 PubMed]<br />
# '''EMN-441:''' Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26596670 PubMed]<br />
# '''EMN01:''' Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26729895 PubMed]<br />
# '''HOVON87/NMSG18:''' Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. [http://www.bloodjournal.org/content/127/9/1109.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26802176 PubMed]<br />
# '''Abstract: Meta-analysis:''' Michel Attal, Antonio Palumbo, Sarah A. Holstein, Valerie Lauwers-Cances, Maria Teresa Petrucci, Paul G. Richardson, Cyrille Hulin, Patrizia Tosi, Kenneth Carl Anderson, Denis Caillot, Valeria Magarotto, Philippe Moreau, Gerald Marit, Zhinuan Yu, Philip L. McCarthy. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): A meta-analysis (MA) of overall survival (OS). J Clin Oncol 34, 2016 (suppl; abstr 8001) [http://meetinglibrary.asco.org/content/168948-176 link to abstract]<br />
<!--<br />
# '''Abstract:''' Korde, Neha; Zingone, Adriana; Kwok, Mary; Manasanch, Elisabet E.; Costello, Rene; Zuchlinski, Diamond; Mulquin, Marcia; Maric, Irina; Calvo, Katherine R; Braylan, Raul C.; Yuan, Constance; Tembhare, Prashant Ramesh; Stetler-Stevenson, Maryalice; Arthur, Diane C; Raffeld, Mark; Xi, Liqiang; Choyke, Peter; Kurdziel, Karen; Lindenberg, Liza; Steinberg, Seth M.; Roschewski, Mark; Landgren, Ola. Phase II Clinical and Correlative Study of Carfilzomib, Lenalidomide, and Dexamethasone (CRd) in Newly Diagnosed Multiple Myeloma (MM) Patients ASH Annual Meeting Abstracts 2012 120: 732 [http://abstracts.hematologylibrary.org/cgi/content/abstract/120/21/732 link to abstract] --><br />
# '''NCI 11-C-0221; NCI 12-C-0107:''' Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. [http://oncology.jamanetwork.com/article.aspx?articleid=2363017 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26181891 PubMed]<br />
# '''IFM 2009:''' Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM 2009 Study. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. [https://www.nejm.org/doi/full/10.1056/NEJMoa1611750 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28379796 PubMed]<br />
# '''UK NCRI Myeloma XI:''' Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Hockaday A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):57-73. Epub 2018 Dec 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30687-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318225/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30559051 PubMed]<br />
<br />
==Rd {{#subobject:945256|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
Rd: '''<u>R</u>'''evlimid (Lenalidomide) & low-dose '''<u>d</u>'''examethasone<br />
===Regimen {{#subobject:ef4eb4|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext Durie et al. 2016 (SWOG S0777)]<br />
| style="background-color:#91cf61" |Non-randomized portion of RCT<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#Rd|Rd]] x 6 versus [[Multiple_myeloma,_induction#RVD|VRd]] x 8<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg PO once per day on days 1 to 21<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1, 8, 15, 22<br />
<br />
'''28-day cycles'''<br />
===References===<br />
# '''SWOG S0777:''' Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)31594-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28017406 PubMed]<br />
<br />
==RP {{#subobject:6261f9|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RP: '''<u>R</u>'''evlimid (Lenalidomide) & '''<u>P</u>'''rednisone<br />
===Variant #1, prednisone 25 mg every other day {{#subobject:2cd1c5|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/127/9/1102.long Magarotto et al. 2016 (EMN01)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#CPR|CPR]] x 9 versus [[Multiple_myeloma,_induction#MPR|MPR]] x 9 versus [[Multiple_myeloma,_induction#Rd|Rd]] x 9<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Prednisone (Sterapred)]] 25 mg PO once every other day<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] or [[:Category:Low molecular weight heparins|LMWH]] or [[Warfarin (Coumadin)]] at physician's discretion (mandatory)<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #2, prednisone 25 mg TIW {{#subobject:5276c5|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html Falco et al. 2012]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#MPR|MPR consolidation]] x 6<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Prednisone (Sterapred)]] 25 mg PO three times per week<br />
<br />
====Supportive medications====<br />
*Thromboprophylaxis: [[Aspirin]] 100 mg PO once per day, taken during [[Lenalidomide (Revlimid)]] treatment (unclear from protocol if this also means off weeks)<br />
*Antiviral prophylaxis if history of VZV.<br />
<br />
'''28-day cycles'''<br />
<br />
===Variant #3, prednisone 50 mg every other day {{#subobject:2acd15|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract Gay et al. 2015 (EMN-441)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Tandem_melphalan.2C_then_auto_HSCT|Tandem high-dose melphalan with autologous hematopoietic stem cell transplants]] versus CRD consolidation<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 10 mg PO once per day on days 1 to 21<br />
*[[Prednisone (Sterapred)]] 50 mg PO once every other day<br />
<br />
'''28-day cycles'''<br />
<br />
===References===<br />
# Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. [https://www.nature.com/leu/journal/v27/n3/full/leu2012271a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22996335 PubMed]<br />
# '''EMN-441:''' Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00389-7/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26596670 PubMed]<br />
# '''EMN01:''' Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. [http://www.bloodjournal.org/content/127/9/1102.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26729895 PubMed]<br />
<br />
==RVD {{#subobject:416bec|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
RVD: '''<u>R</u>'''evlimid (Lenalidomide), '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone<br />
<br>VDR: '''<u>V</u>'''elcade (Bortezomib), '''<u>D</u>'''examethasone, '''<u>R</u>'''evlimid (Lenalidomide)<br />
<br>VRD: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), '''<u>D</u>'''examethasone<br />
<br>VRd: '''<u>V</u>'''elcade (Bortezomib), '''<u>R</u>'''evlimid (Lenalidomide), low-dose '''<u>d</u>'''examethasone<br />
===Variant #1, 3-year course {{#subobject:8392a1|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879104/ Nair et al. 2010 (2006-66)]<br />
|style="background-color:#91cf61"|Non-randomized<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*VTD-PACE consolidation (per Total Therapy 3 protocol)<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 15 mg PO once per day on days 1 to 20, then 5 mg PO once per day on days 21 to 28<br />
*[[Bortezomib (Velcade)]] as follows:<br />
**Year 1: 1 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
**Years 2 & 3: 1 mg/m<sup>2</sup> IV once per week<br />
*[[Dexamethasone (Decadron)]] as follows:<br />
<br />
'''3-year course'''<br />
<br />
===Variant #2, Indefinite {{#subobject:b97d68|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324254/ Richardson et al. 2010]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#RVD|RVD]] x 4 to 8 cycles<br />
====Chemotherapy====<br />
*[[Lenalidomide (Revlimid)]] 25 mg (or previously tolerated dose) PO once per day on days 1 to 14<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> (or previously tolerated dose) IV once per day on days 1 & 8<br />
*[[Dexamethasone (Decadron)]] 20 mg (or previously tolerated dose) PO once per day on days 1, 2, 8, 9<br />
<br />
====Supportive medications====<br />
*[[Aspirin]] 81 mg or 325 mg PO once per day <br />
*[[:Category:Antivirals |Antiviral therapy]], such as [[Acyclovir (Zovirax)]] 400 mg PO once per day <br />
*[[:Category:Bisphosphonates|Bisphosphonate]]<br />
<br />
'''21-day cycles'''<br />
===References===<br />
# '''2006-66:''' Nair B, van Rhee F, Shaughnessy JD Jr, Anaissie E, Szymonifka J, Hoering A, Alsayed Y, Waheed S, Crowley J, Barlogie B. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood. 2010 May 27;115(21):4168-73. Epub 2010 Feb 2. [http://www.bloodjournal.org/content/115/21/4168.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879104/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20124509 PubMed]<br />
# Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. [http://www.bloodjournal.org/content/116/5/679.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324254/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20385792 PubMed]<br />
# '''Retrospective:''' Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar;28(3):690-3. Epub 2013 Nov 13. [https://www.nature.com/leu/journal/v28/n3/full/leu2013335a.html link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24220275 PubMed]<br />
<br />
==Thalidomide monotherapy {{#subobject:9f2412|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Variant #1, 50 mg/day x 2 years {{#subobject:c09c56|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (HOVON-65)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Bortezomib_monotherapy_2|Bortezomib]]<br />
|style="background-color:#d73027"|Inferior PFS (*)<br />
|-<br />
|[http://jco.ascopubs.org/content/30/24/2946.long Sonneveld et al. 2012 (GMMG-HD4)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Bortezomib_monotherapy_2|Bortezomib]]<br />
|style="background-color:#d73027"|Inferior PFS (*)<br />
|-<br />
|}<br />
''Note that in the initial publication, this arm seemed to have an overall survival disadvantage; this was no longer present in the updated report of 2017; PFS was the primary endpoint. Observed efficacy is for induction PAD, then transplant, then maintenance bortezomib compared with induction VAD, then transplant, then maintenance thalidomide. Treatment starts 4 weeks after the final autologous hematopoietic stem cell transplant.''<br />
====Preceding treatment====<br />
*HOVON-65: [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
*GMMG-HD4: [[#Tandem_melphalan.2C_then_auto_HSCT|High-dose melphalan with tandem autologous hematopoietic stem cell transplants]]<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day<br />
<br />
'''2-year course'''<br />
<br />
===Variant #2, 50 mg/d, indefinite {{#subobject:dbd3f3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/19/3160.long Wijermans et al. 2010 (HOVON 49)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
| style="background-color:#d3d3d3" |<br />
| style="background-color:#d3d3d3" |<br />
|-<br />
|[http://www.bloodjournal.org/content/115/6/1113 Lokhorst et al. 2009 (HOVON-50)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Complex_multipart_regimens#HOVON-50|See link]]<br />
|style="background-color:#1a9850"|[[Complex_multipart_regimens#HOVON-50|See link]]<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*HOVON 49: [[Multiple_myeloma,_induction#MPT|MPT]] x 8<br />
*HOVON-50: [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|single]] or [[Multiple_myeloma,_consolidation_and_maintenance#Tandem_melphalan.2C_then_auto_HSCT|tandem]] melphalan auto HSCT<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day<br />
<br />
====Supportive medications====<br />
*'''HOVON 49:''' [[:Category:Bisphosphonates|Bisphosphonate]] use recommended with [[Pamidronate (Aredia)]] or [[Clodronate (Bonefos)]]; "a maximum treatment period of 2 years was recommended in patients without active disease."<br />
*'''HOVON 49:''' During maintenance therapy, "low-dose [[Aspirin]] was advised"<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #3, 50 -> 100 mg/d, indefinite {{#subobject:24fe5b|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ Morgan et al. 2010 (MRC Myeloma IX)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Observation|Observation]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Intensive treatment pathway: [[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]<br />
*Non-intensive treatment pathway: [[Multiple_myeloma,_induction#CTD|CTDa]] versus [[Multiple_myeloma_-_historical#MP_.28Prednisolone.29|MP]]<br />
<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] as follows:<br />
**Weeks 1 to 4: 50 mg PO once per day<br />
**Week 5 onwards: 100 mg PO once per day<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #4, 100 mg/day x 3 years {{#subobject:5b0623|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|rowspan=2|[http://www.bloodjournal.org/content/120/8/1589.long Rosiñol et al. 2012 (GEM05/MENOS65)]<br />
|rowspan=2 style="background-color:#1a9851"|Phase III (E)<br />
|1. [[Multiple_myeloma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]<br />
|style="background-color:#d3d3d3"|Not reported<br />
|-<br />
|2. [[#VT|TV]]<br />
|style="background-color:#fc8d59"|Seems to have inferior PFS (*)<br />
|-<br />
|}<br />
''Note: Reported efficacy for GEM05/MENOS65 is based on the 2017 update.''<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous HSCT]]<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
<br />
'''3-year course'''<br />
<br />
===Variant #5, 100 mg/d, indefinite {{#subobject:596043|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2806%2968338-4/fulltext Palumbo et al. 2006]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ Stewart et al. 2015 (ECOG E1A06)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|style="background-color:#d3d3d3"|<br />
|style="background-color:#d3d3d3"|<br />
|-<br />
|[http://www.bloodjournal.org/content/127/9/1109.long Zweegman et al. 2016 (HOVON87/NMSG18)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#Lenalidomide_monotherapy|Lenalidomide]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*Palumbo et al. 2006: [[Multiple_myeloma,_induction#MPT|MPT]] x 6<br />
*ECOG E1A06: [[Multiple_myeloma,_induction#MPT|MPT]] x 12<br />
*HOVON87/NMSG18: [[Multiple_myeloma,_induction#MPT|MPT]] x 9<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
<br />
====Supportive medications====<br />
*Per ECOG E1A06, [[Aspirin]] was required (dose not specified)<br />
**Per ECOG E1A06, full anticoagulation was used for patients at "higher risk" for DVT<br />
*Per ECOG E1A06, [[Pamidronate (Aredia)]] 90 mg IV once per month recommended for patients with "active bone disease"<br />
<br />
'''Continued indefinitely'''<br />
<br />
===Variant #6, 400 mg/day x 18 months {{#subobject:962746|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[https://www.nature.com/bmt/journal/v37/n9/full/1705339a.html Sahebi et al. 2006]<br />
|style="background-color:#91cf61"|Phase II<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day, escalated by 50 mg every week to a target dose of 400 mg PO once per day<br />
<br />
====Supportive medications====<br />
*[[:Category:Bisphosphonates|Bisphosphonate]] once per month<br />
*Vitamin B6<br />
<br />
'''18 months of treatment or 6 months past CR, whichever comes first'''<br />
<br />
===Variant #7, 400 mg/d, indefinite {{#subobject:767bfd|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/108/10/3289.long Attal et al. 2006 (IFM 99-02)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Observation|Observation]]<br />
|style="background-color:#1a9850"|Superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*VAD x 3 to 4, then [[#Tandem_melphalan.2C_then_auto_HSCT|high-dose melphalan with tandem autologous hematopoietic stem cell transplant]]<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 400 mg PO once per day<br />
**Dose reductions to a minimum of 50 mg PO once per day were allowed<br />
<br />
'''Continued indefinitely'''<br />
<br />
===References===<br />
# Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network (GIMEMA). Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2806%2968338-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16530576 PubMed]<br />
## '''Update:''' Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. [http://www.bloodjournal.org/content/112/8/3107.long link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/18505783 PubMed]<br />
# Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P, Krishnan A, Rodriguez R, Nakamura R, Nademanee A, Popplewell L, Frankel P, Ruel C, Tin R, Ilieva P, Forman SJ, Somlo G. Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma. Bone Marrow Transplant. 2006 May;37(9):825-9. [https://www.nature.com/bmt/journal/v37/n9/full/1705339a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16565743 PubMed]<br />
# '''IFM 99-02:''' Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. [http://www.bloodjournal.org/content/108/10/3289.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/16873668 PubMed]<br />
## '''Update:''' Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. [http://jco.ascopubs.org/content/28/7/1209.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2834471/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20085933 PubMed]<br />
# '''**RETRACTED**''' Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood. 2008 Feb 15;111(4):1805-10. Epub 2007 Sep 17. [http://www.bloodjournal.org/content/111/4/1805.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17875806 PubMed] '''**RETRACTED**'''<br />
<!-- Presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 7, 2008. --><br />
# '''HOVON-50:''' Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19880501 PubMed]<br />
## '''Update:''' van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(18)30149-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30290905 PubMed]<br />
# '''HOVON 49:''' Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. [http://jco.ascopubs.org/content/28/19/3160.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20516439 PubMed]<br />
# '''MRC Myeloma IX:''' Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62051-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639680/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21131037 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. [http://www.bloodjournal.org/content/118/5/1231.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152492/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21652683 PubMed]<br />
## '''Update:''' Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. [http://www.bloodjournal.org/content/119/1/7.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22021371 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. [http://www.haematologica.org/content/97/3/442.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291601/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22058209 PubMed]<br />
## '''Update:''' Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. [http://clincancerres.aacrjournals.org/content/19/21/6030.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23995858 PubMed]<br />
# '''GEM05/MENOS65:''' Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. [http://www.bloodjournal.org/content/120/8/1589.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22791289 PubMed]<br />
## '''Update:''' Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. [https://www.nature.com/leu/journal/v31/n9/full/leu201735a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28111466 PubMed]<br />
# '''HOVON-65/GMMG-HD4:''' Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. [http://jco.ascopubs.org/content/30/24/2946.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22802322 PubMed]<br />
## '''Subgroup analysis:''' Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. [http://www.bloodjournal.org/content/119/4/940.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22160383 PubMed]<br />
## '''Update:''' Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. [https://www.nature.com/articles/leu2017211 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28761118 PubMed]<br />
# Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. [http://www.bloodjournal.org/content/126/11/1294.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566809/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26157076 PubMed]<br />
# Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. [http://www.bloodjournal.org/content/127/9/1109.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/26802176 PubMed]<br />
<br />
==TD {{#subobject:3906a8|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
TD: '''<u>T</u>'''halidomide, '''<u>D</u>'''examethasone<br />
<br>Thal-Dex: '''<u>Thal</u>'''idomide, '''<u>Dex</u>'''amethasone<br />
===Regimen {{#subobject:e146e3|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1002/ajh.23274/full Maiolino et al. 2012]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Dexamethasone_monotherapy_2|Dexamethasone]]<br />
|style="background-color:#1a9850"|Superior PFS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous hematopoietic stem cell transplant]]<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day<br />
*[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4<br />
<br />
'''28-day cycle for 12 months or until disease progression'''<br />
<br />
===References===<br />
# Krishnan A, Pasquini MC, Logan B, Stadtmauer EA, Vesole DH, Alyea E 3rd, Antin JH, Comenzo R, Goodman S, Hari P, Laport G, Qazilbash MH, Rowley S, Sahebi F, Somlo G, Vogl DT, Weisdorf D, Ewell M, Wu J, Geller NL, Horowitz MM, Giralt S, Maloney DG; Blood Marrow Transplant Clinical Trials Network (BMT CTN). Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. Lancet Oncol. 2011 Dec;12(13):1195-203. Epub 2011 Sep 29. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3611089/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21962393 PubMed]<br />
<!-- This work was presented in part at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, 2008 and at the XII International Myeloma Workshop, Washington, DC, 2009. --><br />
# Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, Miranda EC, Quero AA, Peres AL, Barros JC, Tanaka P, Magalhães RP, Rego EM, Lorand-Metze I, Lima CS, Renault IZ, Braggio E, Chiattone C, Nucci M, de Souza CA; Brazilian Multiple Myeloma Study Group (BMMSG/GEMOH). Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012 Oct;87(10):948-52. Epub 2012 Jun 23. [https://onlinelibrary.wiley.com/doi/10.1002/ajh.23274/full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22730113 PubMed]<br />
<br />
==Thalidomide & Prednisolone {{#subobject:6f8a22|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
===Regimen {{#subobject:96e048|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://jco.ascopubs.org/content/27/11/1788.long Spencer et al. 2009 (ALLG MM6)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Prednisolone_monotherapy|Prednisolone]]<br />
|style="background-color:#1a9850"|Superior OS<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & auto HSCT]]<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day, increased to 200 mg PO once per day after 14 days (if tolerated)<br />
*[[Prednisolone (Millipred)]] 50 mg PO once every other day <br />
<br />
'''Thalidomide stopped after 12 months; prednisolone continued indefinitely'''<br />
<br />
===References===<br />
<!-- Presented in part at the 48th Annual Meeting of the American Society of Hematology, Orlando, FL, December 9-12, 2006; and at the XIth International Myeloma Workshop, Kos Island, Greece, June 25-30, 2007. --><br />
# '''ALLG MM6:''' Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009 Apr 10;27(11):1788-93. Epub 2009 Mar 9. [http://jco.ascopubs.org/content/27/11/1788.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19273705 PubMed]<br />
## '''Subgroup analysis:''' Ho PJ, Brown RD, Spencer A, Jeffels M, Daniher D, Gibson J, Joshua DE. Thalidomide consolidation improves progression-free survival in myeloma with normal but not up-regulated expression of fibroblast growth factor receptor 3: analysis from the Australasian Leukaemia and Lymphoma Group MM6 clinical trial. Leuk Lymphoma. 2012 Sep;53(9):1728-34. Epub 2012 Mar 13. [https://www.tandfonline.com/doi/full/10.3109/10428194.2012.664842 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22329352 PubMed]<br />
<br />
==Thalidomide & Prednisone {{#subobject:c74709|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
<br />
===Regimen {{#subobject:ff7fc7|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 20%"|Study<br />
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 20%"|Comparator<br />
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
!style="width: 20%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]<br />
|-<br />
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587317/ Stewart et al. 2013 (NCIC CTG Myeloma 10)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[Multiple_myeloma_-_historical#Observation|Observation]]<br />
|style="background-color:#1a9851"|Improved PFS<br />
|style="background-color:#ffffbe"|Decreased QOL<br />
|-<br />
|}<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan with autologous hematopoietic stem cell transplant]]<br />
====Chemotherapy====<br />
*[[Thalidomide (Thalomid)]] 200 mg PO once per day <br />
*[[Prednisone (Sterapred)]] 50 mg PO once every other day<br />
<br />
====Supportive medications====<br />
*"[[:Category:Bisphosphonates|Bisphosphonates]], histamine-2 blockers, and laxatives were recommended"<br />
*"Anticoagulant and antiplatelet medications were not mandated"<br />
<br />
'''Four years or until disease progression'''<br />
<br />
===References===<br />
# Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013 Feb 28;121(9):1517-23. Epub 2013 Jan 7. [http://www.bloodjournal.org/content/121/9/1517.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587317/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23297129 PubMed]<br />
<br />
==VD {{#subobject:f25dc6|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
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|}<br />
VD: '''<u>V</u>'''elcade (Bortezomib) & '''<u>D</u>'''examethasone<br />
===Regimen {{#subobject:8ce3fb|Variant=1}}===<br />
{| class="wikitable" style="width: 75%; text-align:center;" <br />
!style="width: 33%"|Study<br />
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 33%"|[[Levels_of_Evidence#Efficacy|Efficacy]]<br />
|-<br />
|[https://onlinelibrary.wiley.com/doi/10.1111/bjh.14536/abstract Berdeja et al. 2017 (SCRI MM 23)]<br />
|style="background-color:#91cf61"|Phase II<br />
|ORR: 91%<br />
|-<br />
|}<br />
''Note: this is the modified treatment schema.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#BBD|BBD]] x 8<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV or SC once on day 1<br />
*[[Dexamethasone (Decadron)]] 20 mg PO once on day 1<br />
<br />
'''14-day cycle for 52 cycles (2 years)'''<br />
<br />
===References===<br />
# '''SCRI MM 23:''' Berdeja JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA Jr, Boccia RV, Donnellan W, Flinn I. Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J Haematol. 2017 Apr;177(2):254-262. Epub 2017 Feb 7. [https://onlinelibrary.wiley.com/doi/10.1111/bjh.14536/abstract link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28169430 PubMed]<br />
<br />
==VP {{#subobject:ee2988|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VP: '''<u>V</u>'''elcade (Bortezomib) & '''<u>P</u>'''rednisone<br />
===Regimen {{#subobject:763da1|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext Mateos et al. 2010 (GEM2005)]<br />
|style="background-color:#1a9851"|Phase III (C)<br />
|[[#VT|VT]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VMP|VMP]] x 6 versus [[Multiple_myeloma,_induction#VTP|VTP]] x 6<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Prednisone (Sterapred)]] 50 mg PO once every other day <br />
<br />
====Supportive medications====<br />
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]<br />
*Prophylactic [[Acyclovir (Zovirax)]] was recommended.<br />
<br />
'''3-month cycle for up to 12 cycles (3 years)'''<br />
<br />
===References===<br />
# '''GEM2005:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739218 PubMed]<br />
## '''Subgroup analysis:''' Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. [http://www.bloodjournal.org/content/118/17/4547.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21900193 PubMed]<br />
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. [http://www.bloodjournal.org/content/120/13/2581 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22889759 PubMed]<br />
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators?. Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. [http://www.bloodjournal.org/content/124/12/1887 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25102853 PubMed]<br />
<br />
==VT {{#subobject:e94510|Regimen=1}}==<br />
{| class="wikitable" style="float:right; margin-left: 5px;"<br />
|-<br />
|[[#top|back to top]]<br />
|}<br />
VT: '''<u>V</u>'''elcade (Bortezomib) & '''<u>T</u>'''halidomide<br />
<br>TV: '''<u>T</u>'''halidomide & '''<u>V</u>'''elcade (Bortezomib)<br />
===Variant #1, 1.3/50 x 2 y {{#subobject:8a32ae|Variant=1}}===<br />
{| class="wikitable" style="width: 50%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
|-<br />
|[http://jco.ascopubs.org/content/28/34/5101.long Palumbo et al. 2010 (GIMEMA MM-03-05)]<br />
|style="background-color:#91cf61"|Non-randomized portion of RCT<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VMPT|VMPT]] x 9<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV bolus once on day 1<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day<br />
<br />
'''14-day cycle for up to 2 years or until disease progression or relapse'''<br />
===Variant #2, 1.3/50 x 3 y {{#subobject:8eb947|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext Mateos et al. 2010 (GEM2005)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|[[#VP|VP]]<br />
|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''<br />
====Preceding treatment====<br />
*[[Multiple_myeloma,_induction#VMP|VMP]] x 6 versus [[Multiple_myeloma,_induction#VTP|VTP]] x 6<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 50 mg PO once per day <br />
<br />
====Supportive medications====<br />
*Patients with bone disease received [[:Category:Bisphosphonates|bisphosphonates]]<br />
*Prophylactic [[Acyclovir (Zovirax)|aciclovir]] was recommended.<br />
*Thromboprophylaxis with either [[aspirin]] or [[:Category:Low_molecular_weight_heparins|low molecular weight heparin]]<br />
<br />
'''3-month cycle for up to 12 cycles (3 years)'''<br />
===Variant #3, 1.3/100 {{#subobject:61320d|Variant=1}}===<br />
{| class="wikitable" style="width: 100%; text-align:center;" <br />
!style="width: 25%"|Study<br />
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]<br />
!style="width: 25%"|Comparator<br />
!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]<br />
|-<br />
|[http://www.bloodjournal.org/content/120/8/1589.long Rosiñol et al. 2012 (GEM05/MENOS65)]<br />
|style="background-color:#1a9851"|Phase III (E)<br />
|1. [[Multiple_myeloma_-_historical#Interferon_alfa-2b_monotherapy|Interferon alfa-2b]]<br> 2. [[#Thalidomide_monotherapy|Thalidomide]]<br />
|style="background-color:#91cf60"|Seems to have superior PFS (*)<br />
|-<br />
|}<br />
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Reported efficacy is based on the 2017 update.''<br />
====Preceding treatment====<br />
*[[#Melphalan.2C_then_auto_HSCT|High-dose melphalan & autologous HCT]]<br />
====Chemotherapy====<br />
*[[Bortezomib (Velcade)]] 1.3 mg/m<sup>2</sup> IV once per day on days 1, 4, 8, 11<br />
*[[Thalidomide (Thalomid)]] 100 mg PO once per day <br />
<br />
'''3-month cycle for up to 12 cycles (3 years)'''<br />
<br />
===References===<br />
# '''GEM2005:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70187-X/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20739218 PubMed]<br />
## '''Subgroup analysis:''' Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. [http://www.bloodjournal.org/content/118/17/4547.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21900193 PubMed]<br />
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. [http://www.bloodjournal.org/content/120/13/2581 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22889759 PubMed]<br />
## '''Update:''' Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators?. Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. [http://www.bloodjournal.org/content/124/12/1887 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25102853 PubMed]<br />
# '''GIMEMA MM-03-05:''' Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. [http://jco.ascopubs.org/content/28/34/5101.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20940200 PubMed]<br />
## '''Post-hoc analysis:''' Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. [http://www.bloodjournal.org/content/116/23/4745.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/20807892 PubMed]<br />
## '''Subgroup analysis:''' Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. [http://www.bloodjournal.org/content/118/22/5759.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21951682 PubMed]<br />
## '''Update:''' Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. [http://jco.ascopubs.org/content/32/7/634.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24449241 PubMed]<br />
# '''GEM05/MENOS65:''' Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; Programa para el Estudio y la Terapéutica de las Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) group. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. [http://www.bloodjournal.org/content/120/8/1589.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22791289 PubMed]<br />
## '''Update:''' Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. [https://www.nature.com/leu/journal/v31/n9/full/leu201735a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28111466 PubMed]<br />
<br />
<section end=1st-consol /><br />
{{#lst:Multiple myeloma|bottom}}<br />
[[Category:Multiple myeloma regimens]]<br />
[[Category:Disease-specific pages]]<br />
[[Category:Plasma cell dyscrasias]]</div>Samuelrubinstein