Difference between revisions of "Multiple myeloma"
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# 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''' [http://www.ncbi.nlm.nih.gov/pubmed/20645430 PubMed] | # 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''' [http://www.ncbi.nlm.nih.gov/pubmed/20645430 PubMed] | ||
# 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://bloodjournal.hematologylibrary.org/content/121/11/1982.full link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23299315 PubMed] | # 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://bloodjournal.hematologylibrary.org/content/121/11/1982.full link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23299315 PubMed] | ||
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==CCd== | ==CCd== | ||
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# '''Update:''' Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. doi: 10.3324/haematol.2012.067793. Epub 2012 Jun 11. [http://www.haematologica.org/content/97/12/1925.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22689676 PubMed] | # '''Update:''' Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. doi: 10.3324/haematol.2012.067793. Epub 2012 Jun 11. [http://www.haematologica.org/content/97/12/1925.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22689676 PubMed] | ||
− | ==Bortezomib & Doxorubicin liposomal== | + | ==Bortezomib, Dexamethasone & Panobinostat== |
− | ===Regimen=== | + | |
+ | ===Regimen, Richardson, et al. 2013 (PANORAMA 2)=== | ||
+ | Level of Evidence: | ||
+ | <span | ||
+ | style="background:#EEEE00; | ||
+ | padding:3px 6px 3px 6px; | ||
+ | border-color:black; | ||
+ | border-width:2px; | ||
+ | border-style:solid;">Phase II</span> | ||
+ | |||
+ | ====Phase 1==== | ||
+ | *[[Bortezomib (Velcade)]] 1.3 mg/m2 IV twice per week | ||
+ | *[[Dexamethasone (Decadron)]] 20 mg PO four times per week (day of and day after bortezomib) | ||
+ | *[[Panobinostat (LBH589)]] 20mg PO three times per week | ||
+ | |||
+ | '''2-weeks on, 1-week off x 8 cycles''' | ||
+ | |||
+ | ====Phase 2==== | ||
+ | *[[Bortezomib (Velcade)]] 1.3 mg/m2 IV once per week on weeks 1, 2, 4, 5 | ||
+ | *[[Dexamethasone (Decadron)]] 20 mg PO twice per week on weeks 1, 2, 4, 5 (day of and day after bortezomib) | ||
+ | *[[Panobinostat (LBH589)]] 20mg PO three times per week on weeks 1, 2, 4, 5 | ||
+ | |||
+ | '''6-week cycles until progression, death, or excess toxicity''' | ||
+ | |||
+ | ===References=== | ||
+ | # Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, Mukhopadhyay S, Ondovik MS, Khan M, Paley CS, Lonial S. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013 Aug 15. [Epub ahead of print] [http://bloodjournal.hematologylibrary.org/content/122/14/2331.full link to original article] '''Contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23950178 PubMed] | ||
+ | |||
+ | ==Bortezomib & Doxorubicin liposomal== | ||
+ | ===Regimen=== | ||
Level of Evidence: | Level of Evidence: | ||
<span | <span | ||
Line 2,294: | Line 2,294: | ||
===References=== | ===References=== | ||
# Dadacaridou M, Papanicolaou X, Maltesas D, Megalakaki C, Patos P, Panteli K, Repousis P, Mitsouli-Mentzikof C. Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients. J BUON. 2007 Jan-Mar;12(1):41 to 4. [http://www.ncbi.nlm.nih.gov/pubmed/17436400 PubMed] | # Dadacaridou M, Papanicolaou X, Maltesas D, Megalakaki C, Patos P, Panteli K, Repousis P, Mitsouli-Mentzikof C. Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients. J BUON. 2007 Jan-Mar;12(1):41 to 4. [http://www.ncbi.nlm.nih.gov/pubmed/17436400 PubMed] | ||
+ | |||
+ | ==Dexamethasone (Decadron)== | ||
+ | ===Regimen, Miguel, et al. 2013 (MM-003)=== | ||
+ | Level of Evidence: | ||
+ | <span | ||
+ | style="background:#00CD00; | ||
+ | padding:3px 6px 3px 6px; | ||
+ | border-color:black; | ||
+ | border-width:2px; | ||
+ | border-style:solid;">Phase III</span> | ||
+ | |||
+ | *[[Dexamethasone (Decadron)]] 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 | ||
+ | |||
+ | '''28-day cycles''', given until disease progression or unacceptable toxicity | ||
+ | |||
+ | ===References=== | ||
+ | # Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Sep 2. pii: S1470-2045(13)70380-2. doi: 10.1016/S1470-2045(13)70380-2. [Epub ahead of print] [http://www.sciencedirect.com/science/article/pii/S1470204513703802 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24007748 PubMed] | ||
==PD== | ==PD== |
Revision as of 16:33, 4 October 2013
Use of this site is subject to you reading and agreeing with the terms set forth in the disclaimer.
Is there a regimen missing from this list? Would you like to share a different dosage/schedule or an additional reference for a regimen? Have you noticed an error? Do you have an idea that will help the site grow to better meet your needs and the needs of many others? You are invited to contribute to the site.
Untreated (including transplant ineligible)
BDD
BDD: Bortezomib, Doxorubicin, Dexamethasone
Regimen
Levels of Evidence: Phase II
This is not specifically a first-line regimen but most patients enrolled on the phase II trial were untreated (50 out of 68)
- Bortezomib (Velcade) 1.0 mg/m2 (route not specified) once per day on days 1, 4, 8, 11
- Patients without grade 3 or 4 toxicity during the first two cycles could have bortezomib dose increased to 1.3 mg/m2 (route not specified) once per day on days 1, 4, 8, 11
- Doxorubicin (Adriamycin) 9 mg/m2 IV once per day on days 1 & 4
- Patients without grade 3 or 4 toxicity during the first two cycles could have number of doxorubicin doses increased to 9 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1, 4, 8, 11
21-day cycles x up to 8 cycles
References
- 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. doi: 10.1200/JCO.2010.28.1238. Epub 2010 Sep 7. link to original article contains verified protocol PubMed
BiRD
BiRD: Biaxin, Revlimid, Dexamethasone
Levels of Evidence: 2013 Phase II
2010
Phase II
Retrospective improved PFS
Retrospective increased toxicity
Regimen
- Clarithromycin (Biaxin) 500 mg PO BID on days 2 to 28 of cycle 1; Clarithromycin (Biaxin) 500 mg PO BID on days 1 to 28 of cycle 2 and thereafter
- Lenalidomide (Revlimid) 25 mg PO once per day on days 3 to 21 of cycle 1; Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21 of cycle 2 and thereafter
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 3, 8, 15, 22 of cycle 1; Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22 of cycle 2 and thereafter
28-week cycles
Supportive medications:
- Aspirin 81 mg PO once per day
- Omeprazole (Prilosec) 20 mg PO once per day
- Trimethoprim/Sulfamethoxazole (Bactrim DS) PO BID, 3 times a week
References
- 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. link to original article contains protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. link to original article contains protocol PubMed
CCd
CCd: Carfilzomib, Cyclophosphamide, dexamethasone
Regimen
Level of Evidence: Phase II
- Carfilzomib (Kyprolis) 20 mg/m2 IV once per day on days 1 & 2 of cycle 1 and Carfilzomib (Kyprolis) 36 mg/m2 IV once per day on days 8, 9, 15, 16 of cycle 1; then Carfilzomib (Kyprolis) 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16 of cycles 2 to 9
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycles x 9 cycles, followed by maintenance therapy:
Maintenance therapy
- Carfilzomib (Kyprolis) 36 mg/m2 IV once per day on days 1, 2, 15, 16
28-day cycles, given until progression of disease or unacceptable toxicity
References
- 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 link to abstract
CRd
CRd: Carfilzomib, Revlimid (lenalidomide), (low-dose) dexamethasone
Regimen
Level of Evidence: Phase II, <20 patients reported
It is not clear from the abstract when the 20 mg/m2 vs. 36 mg/m2 dose of carfilzomib is used, nor was it clear what doses were used with oral vs. IV dexamethasone.
- Carfilzomib (Kyprolis) 20 or 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 10 or 20 mg IV/PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
28-day cycles x 8 cycles; patients who had at least stable disease then received:
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycles x 12 cycles
References
- 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 link to abstract
CTD, CTDa
CTD: Cyclophosphamide, Thalidomide, Dexamethasone
CTDa: Cyclophosphamide, Thalidomide, Dexamethasone, attenuated
Regimen #1, Morgan, et al. 2011 (CTDa, MRC Myeloma IX)
Level of Evidence: Phase III
CTDa is intended for elderly or non-transplant-eligible patients
- Cyclophosphamide (Cytoxan) 500 mg PO once per week
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 28; dose is increased every 4 weeks in 50 mg increments, up to a maximum dose of 200 mg PO once per day
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 15 to 18
28-day cycles x 6 to 9 cycles
Supportive medications:
- For the first 12 weeks of treatment, thromboprophylaxis--for example, with Warfarin (Coumadin) or low molecular weight heparin--was recommended
- Patients in the study were randomized to a bisphosphonate and received one of the following until progression:
- Sodium clodronate (Bonefos) 1600 mg PO once per day
- Zoledronic acid (Zometa) 4 mg IV once every 21 to 28 days
Regimen #2, Morgan, et al. 2012 (CTD, MRC Myeloma IX)
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 500 mg PO once per week
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21, increasing to 200 mg PO once per day "if tolerated"
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 12 to 15
21-day cycles x up to 6 cycles
Supportive medications:
- 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 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. link to original article PubMed
- Patients in the study were randomized to a bisphosphonate and received one of the following until progression:
- Sodium clodronate (Bonefos) 1600 mg PO once per day
- Zoledronic acid (Zometa) 4 mg IV once every 21 to 28 days
References
- 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. doi: 10.1182/blood-2011-02-338665. Epub 2011 Jun 7. link to original article contains verified protocol PubMed
- 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. doi: 10.3324/haematol.2011.043372. Epub 2011 Nov 4. link to original article contains verified protocol PubMed
CVAD
CVAD: Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone
Regimen, Morgan et al. 2012 (MRC Myeloma IX)
Level of Evidence: Phase III
The reference paper has unclear wording about the schedule and total number of doses of vincristine and doxorubicin. Please contact the editors of this site if you are able to provide a clarification.
- Cyclophosphamide (Cytoxan) 500 mg PO once per week
- Vincristine (Oncovin) 0.4 mg IV once per day on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 12 to 15
21-day cycles x up to 6 cycles
Supportive medications:
- Patients in the study were randomized to a bisphosphonate and received one of the following until progression:
- Sodium clodronate (Bonefos) 1600 mg PO once per day
- Zoledronic acid (Zometa) 4 mg IV once every 21 to 28 days
References
- 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. doi: 10.3324/haematol.2011.043372. Epub 2011 Nov 4. link to original article contains verified protocol--see comment above PubMed
CyBorD, CVD, VCD
CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone
CVD: Cyclophosphamide, Velcade, Dexamethasone
Regimen #1, Reeder, et al. 2009
Level of Evidence: Phase II
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15, 22
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
28-day cycles x 4 to 12 cycles
Supportive medications:
- Proton pump inhibitor (PPI)
- Acyclovir (Zovirax)
- Quinolone antibiotic
- Antifungal mouthwash recommended
Regimen #2, Kumar, et al. 2012 (EVOLUTION/VDC-mod)
Level of Evidence: Phase II
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1, 8, 15
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
21-day cycles x 8 cycles, then
Maintenance therapy:
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
42-day cycles x 4 cycles
Supportive medications:
- Aspirin 325 mg PO once per day
- Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
- PCP prophylaxis recommended
- Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
- Bisphosphonates could be used "as necessary"
Regimen #3, Kumar, et al. 2012 (EVOLUTION/VDC)
Level of Evidence: Phase II
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
21-day cycles x 8 cycles, then
Maintenance therapy:
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
42-day cycles x 4 cycles
Supportive medications:
- Aspirin 325 mg PO once per day
- Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
- PCP prophylaxis recommended
- Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
- Bisphosphonates could be used "as necessary"
Regimen #4, Reeder, et al. 2010 (once per week bortezomib)
This regimen was described in a letter to the editor of Blood.
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15, 22
- Bortezomib (Velcade) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 during cycles 1 and 2; Dexamethasone (Decadron) 40 mg PO once per week during cycles 3 and 4.
28-day cycles x 4 cycles
References
- 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. link to original article contains protocol PubMed
- 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. doi: 10.1182/blood-2010-02-271676. link to original letter contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
DEX (Dexamethasone)
DEXamethasone
Regimen #1, Facon et al. 2006 (IFM 95-01)
Level of Evidence: Phase III
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 for cycles 1 to 2; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycles 3 to 12
6-week cycles x 12 cycles
Regimen #2, Rajkumar, et al. 2006
Level of Evidence: Phase III
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 on odd-numbered cycles; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of even-numbered cycles
28-day cycles
Regimen #3, Rajkumar, et al. 2008
Level of Evidence: Phase III
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of cycles 1 to 4; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycle 5 and thereafter
28-day cycles
References
- Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group. 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. link to original article contains protocol PubMed
- Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006 Feb 15;107(4):1292-8. Epub 2005 Sep 20. link to original paper contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
DEX-IFN
DEXamethasone, IFN: Interferon alfa-2b
Regimen, Facon et al. 2006 (IFM 95-01)
Level of Evidence: Phase III
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 for cycles 1 to 2; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycles 3 to 12
- Interferon alfa-2b (Intron-A) 3 million units SC 3 times per week; start with dexamethasone and stop on on day 42 of the last cycle of dexamethasone
6-week cycles x 12 cycles
References
- Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006 Feb 15;107(4):1292-8. Epub 2005 Sep 20. link to original paper contains protocol PubMed
DVD, DVd, VAD doxil
DVD: Doxil, Vincristine, Dexamethasone
Regimen #1, Hussein, et al. 2002
Level of Evidence: Phase II
- Doxorubicin liposomal (Doxil) 40 mg/m2 IV once on day 1
- Vincristine (Oncovin) 2 mg IV once on day 1
- Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4
4-week cycles x 6 to 8 cycles
Supportive medications:
- Vitamin B6 200 mg PO once per day to help reduce risk of palmar-plantar erythrodysesthesia (PPE)
Regimen #2, Rifkin, et al. 2006
Level of Evidence: Phase III
- Doxorubicin liposomal (Doxil) 40 mg/m2 IV over 1 hour once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose per cycle capped at 2 mg) IV over 5 minutes once on day 1
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
4-week cycles, given until maximal response, progression of disease, or unacceptable toxicity
Regimen #3, Dimopoulos, et al. 2003 & Zervas, et al. 2007 (VAD doxil)
Level of Evidence: Phase III
- Vincristine (Oncovin) 2 mg IV once on day 1
- Doxorubicin liposomal (Doxil) 40 mg/m2 IV over 1 hour once on day 1
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4; in cycles 1 & 3, Dexamethasone (Decadron) 40 mg PO is also given once per day on days 9 to 12, 17 to 20
4-week cycles x 4 cycles
Supportive medications (which were in the cited Segeren, et al. 1999 reference):
- Fluconazole (Diflucan) 200 mg PO once per day
- Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO BID for "prophylaxis"
References
- 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. link to original article contains protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
MP, M-DEX
MP: Melphalan, Prednisone/rednisolone
M-DEX: Melphalan, DEXamethasone
Regimen #1, Facon, et al. 2006 (IFM 95-01)
Level of Evidence: Phase III
- Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
- Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
6-week cycles x 12 cycles
Regimen #2, San Miguel, et al. 2008, Mateos, et al. 2010 (VISTA)
Level of Evidence: Phase III
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
6-week cycles x 9 cycles
Regimen #3
Note: Though this regimen is listed in several online references, no primary reference for this exact regimen could be found. Specifically, some references cite the Facon, et al. 2006 paper for this regimen, but this regimen is not in that paper. Many additional variations of MP can be found in the Myeloma Trialists' Collaborative Group 1998 Journal of Clinical Oncology paper referenced below.
- Melphalan (Alkeran) 0.15 mg/kg PO once daily on days 1 to 7
- Prednisone (Sterapred) 20 mg PO TID on days 1 to 7
6-week cycles
Regimen #4, Facon, et al. 2006, Facon, et al. 2007 (IFM 95-01, IFM 99-06)
Level of Evidence: Phase III
- Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 for cycles 1 to 2; 40 mg PO once per day on days 1 to 4 of cycles 3 to 12
6-week cycles x 12 cycles
Regimen #5, Hulin, et al. 2009 (IFM 01/01)
Level of Evidence: Phase III
- Melphalan (Alkeran) 0.2 mg/kg PO once per day on days 1 to 4
- Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
6-week cycles x 12 cycles
Regimen #6, Palumbo, et al. 2012 (MM-015)
Level of Evidence: Phase III
- Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
- Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
28-day cycles x 9 cycles
Supportive medications:
- Aspirin 75 to 100 mg PO once per day as thromboprophylaxis
Regimen #7, Wijermans, et al. 2010 (HOVON 49)
Level of Evidence: Phase III
- Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 5
- Prednisone (Sterapred) 1 mg/kg PO once per day on days 1 to 5
28-day cycles x 8 cycles
Supportive medications:
- Bisphosphonate use recommended with Pamidronate (Aredia) or Clodronate (Bonefos); "a maximum treatment period of 2 years was recommended in patients without active disease."
Regimen #8, Morgan, et al. 2011 (MRC Myeloma IX study)
Level of Evidence: Phase III
- Melphalan (Alkeran) 7 mg/m2 PO once per day on days 1 to 4
- Prednisolone (Millipred) 40 mg PO once per day on days 1 to 4
28-day cycles x 6 to 9 cycles
Supportive medications:
- Patients in the study were randomized to a bisphosphonate and received one of the following until progression:
- Sodium clodronate (Bonefos) 1600 mg PO once per day
- Zoledronic acid (Zometa) 4 mg IV once every 21 to 28 days
Regimen #9, Palumbo, et al. 2006
Level of Evidence: Phase III
- Melphalan (Alkeran) 4 mg/m2 PO once per day on days 1 to 7
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 7
28-day cycles x 6 cycles
References
- Kyle RA. Monoclonal gammopathy and multiple myeloma in the elderly. Baillieres Clin Haematol. 1987 Jun;1(2):533-57. PubMed
- Myeloma Trialists' Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998 Dec;16(12):3832-42. link to original article contains protocol PubMed
- Facon T, Mary JY, Pégourie B, Attal M, Renaud M, Sadoun A, Voillat L, Dorvaux V, Hulin C, Lepeu G, Harousseau JL, Eschard JP, Ferrant A, Blanc M, Maloisel F, Orfeuvre H, Rossi JF, Azaïs I, Monconduit M, Collet P, Anglaret B, Yakoub-Agha I, Wetterwald M, Eghbali H, Vekemans MC, Maisonneuve H, Troncy J, Grosbois B, Doyen C, Thyss A, Jaubert J, Casassus P, Thielemans B, Bataille R; Intergroupe Francophone du Myélome (IFM) group. Dexamethasone-based regimens versus melphalan-prednisone for elderly multiple myeloma patients ineligible for high-dose therapy. Blood. 2006 Feb 15;107(4):1292-8. Epub 2005 Sep 20. link to original paper contains verified protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. link to original article contains protocol PubMed content property of HemOnc.org
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. doi: 10.1182/blood-2011-02-338665. Epub 2011 Jun 7. link to original article contains verified protocol PubMed
- Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jędrzejczak 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. link to original article contains verified protocol PubMed
- 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. doi: 10.1200/JCO.2009.26.1610. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
MPR, MPR-R, MPL
MPL: Melphalan, Prednisone, Lenalidomide
MPR: Melphalan, Prednisone, Revlimid
MPR-R: Melphalan, Prednisone, Revlimid, Revlimid maintenance
Regimen #1, Palumbo, et al. 2007 & Palumbo, et al. 2012 (MPR-R)
Level of Evidence: Phase III
Induction therapy
- Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
- Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycles x 9 cycles, then proceed to maintenance therapy
Maintenance therapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycles, to continue until relapsed or refractory disease
Supportive medications (varies depending on reference):
- Palumbo et al. 2012: Aspirin 75 to 100 mg PO once per day as thromboprophylaxis
- Palumbo et al. 2007: Ciprofloxacin (Cipro) 500 mg PO BID and Aspirin 100 mg PO once per day
Regimen #2, Palumbo, et al. 2012 (MM-015)
Level of Evidence: Phase III
- Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
- Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycles x 9 cycles
Supportive medications:
- Aspirin 75 to 100 mg PO once per day as thromboprophylaxis
References
- 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. link to original article contains verified protocol PubMed
- Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jędrzejczak 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. link to original article contains verified protocol PubMed
MPT
MPT: Melphalan, Prednisone, Thalidomide
Regimen #1, Facon, et al. 2007 (IFM 99-06)
Level of Evidence: Phase III
- Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
- Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
- Thalidomide (Thalomid) 200 mg PO once per day , increased as tolerated after to 4 weeks on therapy to maximum dose of 400 mg once per day, given on days 1 to 42
42-day cycles x 12 cycles
Regimen #2, Palumbo, et al. 2006 (GIMEMA)
Level of Evidence: Phase III
Induction therapy
- Melphalan (Alkeran) 4 mg/m2 PO once per day on days 1 to 7
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 7
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28
Supportive medications:
- Enoxaparin (Lovenox) 40 mg SC once per day on days 1 to 28 of cycles 1 to 4
28-day cycles x 6 cycles, then proceed to maintenance therapy
Maintenance therapy
- Thalidomide (Thalomid) 100 mg PO once per day until evidence of relapse or refractory disease
Regimen #3, Hulin, et al. 2009 (IFM 01/01)
Level of Evidence: Phase III
- Melphalan (Alkeran) 0.2 mg/kg PO once per day on days 1 to 4
- Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
- Thalidomide (Thalomid) 100 mg PO once per day
42-day cycles x 12 cycles
Regimen #4, Wijermans, et al. 2010 (HOVON 49)
Level of Evidence: Phase III
Induction therapy
- Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 5
- Prednisone (Sterapred) 1 mg/kg PO once per day on days 1 to 5
- Thalidomide (Thalomid) 200 mg PO once per day
28-day cycles x 8 cycles, then
- Thalidomide (Thalomid) 200 mg PO once per day
28-day course, then
Maintenance therapy
- Thalidomide (Thalomid) 50 mg PO once per day until progression
Supportive medications (for induction & maintenance periods):
- Bisphosphonate use recommended with Pamidronate (Aredia) or Clodronate (Bonefos); "a maximum treatment period of 2 years was recommended in patients without active disease."
- Recommended thromboprophylaxis:
- During induction therapy, low molecular weight heparin use recommended with nadroparin 2,850 units anti-Xa (for patients >90 kg, dose of 5,700 units anti-Xa)
- During maintenance therapy, "low-dose aspirin was advised"
References
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed content property of HemOnc.org
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. doi: 10.1200/JCO.2009.26.1610. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
Rd
Rd: Revlimid, low dose dexamethasone
Regimen, Rajkumar, et al. 2010 (ECOG E4A03) & Gay, et al. 2010
Level of Evidence: Phase III
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycles, either given x 4 cycles prior to transplant, or given until progression of disease or unacceptable toxicity
Supportive medications (as described in Rajkumar, et al. 2010):
- One of the following bisphosphonates:
- Pamidronate (Aredia) 90 mg IV over 2 to 4 hours once every 4 weeks
- Zoledronic acid (Zometa) 4 mg IV over 15 minutes once every 4 weeks
- Thromboprophylaxis required
References
- Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group. 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
RD, RevDex
RD: Revlimid, Dexamethasone
RevDex: Revlimid, Dexamethasone
Regimen #1, Rajkumar, et al. 2010
Level of Evidence: Phase III
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
28-day cycles
Supportive medications:
- One of the following bisphosphonates:
- Pamidronate (Aredia) 90 mg IV over 2 to 4 hours once every 28 days
- Zoledronic acid (Zometa) 4 mg IV over 15 minutes once every 28 days
- "Thromboprophylaxis" aspirin (80 mg or 325 mg per physician discretion) once per day as thrombosis prophylaxis.
Regimen #2, Rajkumar, et al. 2005
Level of Evidence: Phase II
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of cycles 1 to 4; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycle 5 and thereafter
28-day cycles, given until progression of disease or unacceptable toxicity
Supportive medications:
- Aspirin 80 mg or 325 mg (depending on physician choice) PO once per day for thromboprophylaxis
References
- 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. link to original article contains protocol PubMed
- Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; Eastern Cooperative Oncology Group. 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. link to original article contains verified protocol PubMed
RVD, VDR, VRD
RVD: Revlimid, Velcade, Dexamethasone
VDR: Velcade, Dexamethasone, Revlimid
VRD: Velcade, Revlimid, Dexamethasone
Regimen #1, Richardson, et al. 2010
Level of Evidence: Phase II
Induction therapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycles x 4 to 8 cycles
Supportive medications:
- Aspirin 81 mg or 325 mg PO once per day
- Antiviral therapy, such as Acyclovir (Zovirax) 400 mg PO once per day
- Bisphosphonate
Maintenance therapy
Patients who responded and tolerated therapy could proceed to maintenance therapy at previously tolerated dose with a different schedule:
- Lenalidomide (Revlimid) 25 mg (or previously tolerated dose) PO once per day on days 1 to 14
- Bortezomib (Velcade) 1.3 mg/m2 (or previously tolerated dose) IV once per day on days 1 & 8
- Dexamethasone (Decadron) 20 mg (or previously tolerated dose) PO once per day on days 1, 2, 8, 9
21-day cycles
Regimen #2, Kumar, et al. 2012 (EVOLUTION)
Level of Evidence: Phase II
Induction therapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
21-day cycles x 8 cycles, then proceed to maintenance therapy
Maintenance therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
42-day cycles x 4 cycles
Supportive medications:
- Aspirin 325 mg PO once per day
- Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
- PCP prophylaxis recommended
- Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
- Bisphosphonates could be used "as necessary"
References
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
RVDC, VDCR
RVDC: Revlimid, Velcade, Dexamethasone, Cyclophosphamide
VDCR: Velcade, Dexamethasone, Cyclophosphamide, Revlimid
Regimen, Kumar et al. 2012 (EVOLUTION)
Level of Evidence: Phase II
Induction therapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
21-day cycles x 8 cycles, then proceed to maintenance therapy
Maintenance therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
42-day cycles x 4 cycles
Supportive medications:
- Aspirin 325 mg PO once per day
- Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
- PCP prophylaxis recommended
- Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
- Bisphosphonates could be used "as necessary"
References
- 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. link to original article contains verified protocol PubMed
TD
TD: Thalidomide, Dexamethasone
Regimen #1, Rajkumar, et al. 2008
Level of Evidence: Phase III
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 14 of cycle 1; Thalidomide (Thalomid) 100 mg PO once per day on days 15 to 28 of cycle 1; Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 28 of cycle 2 and thereafter
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of cycles 1 to 4; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycle 5 and thereafter
28-day cycles
Regimen #2, Rajkumar, et al. 2002 & Rajkumar, et al. 2006
Level of Evidence: Phase III
- Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 28
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 on odd-numbered cycles; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of even-numbered cycles
28-day cycles
Regimen #3, Cavo, et al. 2010 & Cavo, et al. 2012 (GIMEMA)
Induction therapy
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 14 of cycle 1; Thalidomide (Thalomid) 200 mg PO once per day on days 15 to 21 of cycle 1; Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 21 of cycles 2 & 3
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
21-day cycles x 3 cycles, then proceed to first stem cell transplant
First stem cell transplant
- Melphalan (Alkeran) 200 mg/m2 (route not specified) once on day -2
- Autologous stem cell rescue
Wait until count recovery, then proceed to thalidomide & dexamethasone therapy
Thalidomide & dexamethasone therapy
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles for 3 to 6 months, then proceed to second stem cell transplant
Second stem cell transplant
- Melphalan (Alkeran) 200 mg/m2 (route not specified) once on day -2
- Autologous stem cell rescue
Wait until 3 months after second transplant, then proceed to thalidomide & dexamethasone therapy
Thalidomide & dexamethasone therapy
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 20 to 23
35-day cycles x 2 cycles, then proceed to dexamethasone maintenance therapy
Dexamethasone maintenance therapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles until progression, relapse, or undue toxicity
Supportive medications:
- Acyclovir (Zovirax) prophylaxis recommended
Regimen #4, Rosiñol, et al. 2012
2012: Phase III Decreased PFS Decreased toxicity
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 14 of cycle 1; Thalidomide (Thalomid) 100 mg PO once per day on days 15 to 28 of cycle 1; Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 28 of cycle 2 and thereafter
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
28-day cycles x 6 cycles
Supportive medications:
- Low-molecular weight heparin or aspirin recommended
References
- 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. link to original article PubMed
- 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. link to original article PubMed
- Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group. 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. doi: 10.1016/S0140-6736(10)61424-9. Epub 2010 Dec 9. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. link to original article PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
VAD (Velcade); PAD
VAD: Velcade, Adriamycin, Dexamethasone
PAD: PS-341, Adriamycin, Dexamethasone
Regimen #1, Broyl, et al. 2010 & Sonneveld, et al. 2012 (HOVON-65/GMMG-HD4)
Level of Evidence: Phase III
Induction therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Doxorubicin (Adriamycin) 9 mg/m2 IV once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
28-day cycles x 3 cycles; stem cells collected 4 to 6 weeks after induction therapy
Supportive medications (described in the appendix of Sonneveld, et al. 2012):
- One of the following bisphosphonates recommended:
- Pamidronate (Aredia) 90 mg IV once every 4 to 6 weeks x at least 2 years
- Zoledronic acid (Zometa) 4 mg IV once every 4 to 6 weeks x at least 2 years
- Ibandronate (Boniva) 6 mg IV once every 4 to 6 weeks x at least 2 years
- "Prophylactic antibiotics" (no further specifics) during induction therapy
- Erythropoietin and pain medications at physician discretion
- One of the following for Herpes zoster prophylaxis throughout bortezomib induction:
- Acyclovir (Zovirax) 800 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)
- Valacyclovir (Valtrex) 1000 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)
Stem-cell transplant
High dose melphalan single (HOVON-65) or tandem (GMMG-HD4)
Maintenance
Bortezomib maintenance x 2 years, starting 4 weeks after last transplant
Regimen #2, Oakervee, et al. 2005
Level of Evidence: Phase II
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
- Doxorubicin (Adriamycin) 4.5 to 9 mg/m2 IV once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18 of cycle 1; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycles 2 to 4
21-day cycles x 4 cycles
References
- 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. link to original article contains protocol PubMed
- Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. Epub 2010 Sep 21. link to original article contains verified protocol PubMed
- 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. doi: 10.1200/JCO.2011.39.6820. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
VAD (Vincristine), VAD-P
VAD: Vincristine, Adriamycin, Dexamethasone
VAD-P: Vincristine, Adriamycin, Dexamethasone, Prednisone
Regimen #1, Barlogie, et al. 1984
Level of Evidence: Phase II
- Vincristine (Oncovin) 0.4 mg/day (total dose per cycle: 1.6 mg) IV continuous infusion over 96 hours on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 96 hours on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
Cycle duration not specified; treatment was given "until a maximum reduction in myeloma protein had occurred." Patients received four additional cycles of therapy beyond their best response.
Supportive medications:
- Cimetidine (Tagamet) prophylaxis (dose not specified)
- Trimethoprim/Sulfamethoxazole prophylaxis (dose not specified)
Regimen #2, Segeren, et al. 1999
Level of Evidence: Phase II
- Vincristine (Oncovin) 0.4 mg IV over 30 minutes once per day on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2 IV over 30 minutes once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of odd-numbered cycles only
4-week cycles
Supportive medications:
- Fluconazole (Diflucan) 200 mg PO once per day
- Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO BID for "prophylaxis"
Regimen #3, Berenson, et al. 2002 (SWOG 9210)
Level of Evidence: Phase III
- Vincristine (Oncovin) 0.4 mg/day (total dose per cycle: 1.6 mg) IV continuous infusion over 4 days on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Poor-risk patients received 6.75 mg/m2/day (total dose 27 mg/m2) in cycle 1, with increase to full dose starting cycle 2 if no undue toxicity
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
- Prednisone (Sterapred) 50 mg PO once per day on days 9, 11, 13, 15, 17, 19
21-day cycles x at least 6 months or until at least 25% regression of disease
Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were then started on prednisone maintenance therapy.
Regimen #4, Dimopoulos, et al. 2003
Level of Evidence: Phase III
- Vincristine (Oncovin) 0.4 mg IV over 30 minutes once per day on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2 IV over 30 minutes once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4; in cycles 1 & 3, Dexamethasone (Decadron) 40 mg PO is also given once per day on days 9 to 12, 17 to 20
4-week cycles x 4 cycles
Supportive medications (which were in the cited Segeren, et al. 1999 reference):
- Fluconazole (Diflucan) 200 mg PO once per day
- Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO BID for "prophylaxis"
Regimen #5, Rifkin, et al. 2006
Level of Evidence: Phase III
- Vincristine (Oncovin) 0.4 mg/day (total dose per cycle: 1.6 mg) IV continuous infusion over 96 hours on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 96 hours on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles
Regimen #6, Harousseau, et al. 2010 (IFM 2005-01)
Level of Evidence: Phase III
- Vincristine (Oncovin) 0.4 mg/day (total dose per cycle: 1.6 mg) IV continuous infusion over 4 days on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of cycles 1 & 2; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycles 3 and thereafter
28-day cycles
Supportive medications:
- Pamidronate (Aredia) 90 mg or Zoledronic acid (Zometa) 4 mg IV once every 28 days until first transplant
- "Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."
Regimen #7, Facon, et al. 2007 (IFM 99-06)
Level of Evidence: Phase III
- Vincristine (Oncovin) 0.4 mg/day (total dose per cycle: 1.6 mg) IV continuous infusion over 4 days on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles x 2 cycles
Followed by stem-cell mobilization and RIC transplant, to be completed
Regimen #8, Broyl, et al. 2010 & Sonneveld, et al. 2012 (HOVON-65/GMMG-HD4)
Level of Evidence: Phase III
Induction therapy
- Vincristine (Oncovin) 0.4 mg IV once per day on days 1 to 4
- Doxorubicin (Adriamycin) 9 mg/m2 IV once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
28-day cycles x 3 cycles; stem cells collected 4 to 6 weeks after induction therapy
Supportive medications (described in the appendix of Sonneveld, et al. 2012):
- One of the following bisphosphonates recommended:
- Pamidronate (Aredia) 90 mg IV once every 4 to 6 weeks x at least 2 years
- Zoledronic acid (Zometa) 4 mg IV once every 4 to 6 weeks x at least 2 years
- Ibandronate (Boniva) 6 mg IV once every 4 to 6 weeks x at least 2 years
- "Prophylactic antibiotics" (no further specifics) during induction therapy
- Erythropoietin and pain medications at physician discretion
- One of the following for Herpes zoster prophylaxis throughout bortezomib induction:
- Acyclovir (Zovirax) 800 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)
- Valacyclovir (Valtrex) 1000 mg PO per day (did not specify whether taken once per day or as a divided twice per day dose)
Stem-cell transplant
High dose melphalan single (HOVON-65) or tandem (GMMG-HD4)
Maintenance
Thalidomide maintenance x 2 years, starting 4 weeks after last transplant
References
- Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med. 1984 May 24;310(21):1353-6. link to original article contains verified protocol PubMed
- Segeren CM, Sonneveld P, van der Holt B, Baars JW, Biesma DH, Cornellissen JJ, Croockewit AJ, Dekker AW, Fibbe WE, Löwenberg B, van Marwijk Kooy M, van Oers MH, Richel DJ, Schouten HC, Vellenga E, Verhoef GE, Wijermans PW, Wittebol S, Lokhorst HM. Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol. 1999 Apr;105(1):127-30. link to original article contains verified protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed content property of HemOnc.org
- 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. link to original article contains protocol PubMed
- Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. Epub 2010 Sep 21. link to original article contains verified protocol PubMed
- 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. doi: 10.1200/JCO.2011.39.6820. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
VAD-P/Q
VAD-P/Q: Vincristine, Adriamycin, Dexamethasone, Prednisone, Quinine
Regimen, Berenson, et al. 2002 (SWOG 9210)
Level of Evidence: Phase III
- Vincristine (Oncovin) 0.4 mg/day (total dose per cycle: 1.6 mg) IV continuous infusion over 4 days on days 2 to 5
- Doxorubicin (Adriamycin) 9 mg/m2/day (total dose per cycle: 36 mg/m2) IV continuous infusion over 4 days on days 2 to 5
- Poor-risk patients received 6.75 mg/m2/day (total dose 27 mg/m2) in cycle 1, with increase to full dose starting cycle 2 if no undue toxicity
- Dexamethasone (Decadron) 40 mg PO once per day on days 2 to 5
- Prednisone (Sterapred) 50 mg PO once per day on days 10, 12, 14, 16, 18, 20
- Quinine (Qualaquin) 400 mg PO TID on days 1 to 6
21-day cycles x at least 6 months or until at least 25% regression of disease
Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were then started on prednisone maintenance therapy.
References
- 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. link to original article contains protocol PubMed
VD (Velcade)
VD: Velcade, Dexamethasone
Regimen, Harousseau, et al. 2010 (IFM 2005-01)
Level of Evidence: Phase III
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12 of cycles 1 & 2; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycles 3 & 4
21-day cycles x 4 cycles
Supportive medications:
- One of the following bisphosphonates recommended:
- Pamidronate (Aredia) 90 mg IV once every 4 weeks until first transplant
- Zoledronic acid (Zometa) 4 mg IV once every 4 weeks until first transplant
- "Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."
References
- 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. link to original article contains verified protocol PubMed
- Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-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. link to original article PubMed
VDD; PAD
VDD: Velcade, Doxil, Dexamethasone
PAD: PS-341, liposomal Adriamycin, Dexamethasone
Regimen #1, Jakubowiak, et al. 2009 & Dytfeld, et al. 2011
Level of Evidence: Phase II
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Doxorubicin liposomal (Doxil) 30 mg/m2 IV once on day 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12 of cycle 1; then Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12 of cycles 2 to 6
21-day cycles x 6 cycles
Supportive medications:
- Low-molecular weight heparin 40 mg SC once per day or Aspirin 81 mg PO once per day for DVT prophylaxis
- Acyclovir (Zovirax) 400 mg PO BID for Herpes zoster prophylaxis
Regimen #2, Palumbo, et al. 2010
Level of Evidence: Phase II
Induction therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Doxorubicin liposomal (Doxil) 30 mg/m2 IV once on day 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18 of cycle 1; then Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycles 2 to 4
21-day cycles x 4 cycles, then proceed to stem cell mobilization & reinfusion
Stem cell mobilization & reinfusion
Paper did not describe the full details
- Stem cell mobilization with Cyclophosphamide (Cytoxan) 3000 mg/m2 and G-CSF 10 mcg/kg
- Melphalan (Alkeran) 100 mg/m2, given twice, then followed by stem-cell reinfusion
Consolidation
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Prednisone (Sterapred) 50 mg PO once every other day
28-day cycles x 4 cycles, then proceed to maintenance therapy
Maintenance
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycles, given until relapsed disease
Supportive medications:
- Aspirin 100 mg PO once per day during lenalidomide treatment
- Acyclovir (Zovirax) recommended during bortezomib therapy
References
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains protocol PubMed
VMP
VMP: Velcade, Melphalan, Prednisone
Regimen #1, San Miguel, et al. 2008, Mateos, et al. 2010 & Palumbo, et al. 2010 (VISTA)
Level of Evidence: Phase III
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32 of cycles 1 to 4; Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 8, 22, 29 of cycles 5 to 9
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
42-day cycles x 9 cycles
Supportive medication:
- Bisphosphonate given to patients with myeloma-associated bone disease unless contraindicated (only mentioned in San Miguel, et al. 2008)
Regimen #2, Palumbo, et al 2010 & Bringhen, et al. 2010 (weekly bortezomib)
Level of Evidence: Post-hoc analysis
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 8, 15, 22
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
35-day cycles x 9 cycles
Regimen #3, Gasparetto, et al. 2010 ("Short-course" bortezomib)
Level of Evidence: Phase II
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Melphalan (Alkeran) 6 mg/m2 PO once per day on days 1 to 7, given at least 1 hour prior to bortezomib
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 7
28-day cycles x up to 6 cycles; treatment could be given beyond 6 cycles at investigator discretion
Supportive medications:
- Bisphosphonates and Acyclovir (Zovirax) recommended
Regimen #4, Mateos, et al. 2010
Level of Evidence: Phase III
Induction therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
42-day cycle x 1 cycle, then
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
35-day cycles x 5 cycles, then
Maintenance therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Only one of the following:
- Prednisone (Sterapred) 50 mg PO once every other day
- Thalidomide (Thalomid) 50 mg PO once per day
3-month cycles x up to 3 years
Supportive medications:
- "Patients with bone disease received bisphosphonates, and prophylactic aciclovir was recommended."
- Patients receiving thalidomide needed to have thromboprophylaxis with either aspirin or low molecular weight heparin
References
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. doi:10.1200/JCO.2010.29.8216. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
- 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. doi: 10.1182/blood-2011-05-353995. Epub 2011 Sep 27. link to original article PubMed
VMPT-VT
VMPT-VT: Velcade, Melphalan, Prednisone, Thalidomide, Velcade maintenance, Thalidomide maintenance
Regimen #1, Palumbo, et al. 2010
Level of Evidence: Phase III
Induction therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32 of cycles 1 to 4; Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 8, 22, 29 of cycles 5 to 9
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 42
42-day cycles x 9 cycles, then
Maintenance therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once on day 1
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 14
14-day cycles x 2 years or until disease progression or relapse
Regimen #2, Palumbo, et al. 2010, Bringhen, et al. 2010
Level of Evidence: Phase III
This represents a mid-protocol change where cycle length was decreased from 6 to 5 weeks and bortezomib was changed to weekly dosing
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 8, 15, 22
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 42
35-day cycles x 9 cycles, then
Maintenance therapy:
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once on day 1
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 14
14-day cycles x 2 years or until disease progression or relapse
References
- 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. doi:10.1200/JCO.2010.29.8216. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. doi: 10.1182/blood-2011-05-353995. Epub 2011 Sep 27. link to original article PubMed
VTD
VTD: Velcade (bortezomib), Thalidomide, Dexamethasone
Regimen #1, Cavo, et al. 2010 & Cavo, et al. 2012 (GIMEMA)
Level of Evidence: Phase III
Induction therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 14 of cycle 1; Thalidomide (Thalomid) 200 mg PO once per day on days 15 to 21 of cycle 1; Thalidomide (Thalomid)200 mg PO once per day on days 1 to 21 of cycles 2 & 3
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycles x 3 cycles, then proceed to first stem cell transplant
First stem cell transplant
- Melphalan (Alkeran) 200 mg/m2 once on day -2
- Autologous stem cell rescue
Wait until count recovery, then proceed to thalidomide & dexamethasone therapy
Thalidomide & dexamethasone therapy
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles for 3 to 6 months, then proceed to second stem cell transplant
Second stem cell transplant
- Melphalan (Alkeran) 200 mg/m2 once on day -2
- Autologous stem cell rescue
Wait until 3 months after second transplant, then proceed to bortezomib, thalidomide, dexamethasone therapy
Bortezomib, thalidomide, dexamethasone therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
35-day cycles x 2 cycles, then proceed to dexamethasone maintenance therapy
Dexamethasone maintenance therapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles, given until progression, relapse, or undue toxicity
Supportive medications:
- Acyclovir (Zovirax) prophylaxis recommended
Regimen #2, Kaufman, et al. 2010
Level of Evidence: Retrospective
- Bortezomib (Velcade) 1.3 mg/m2 IV once daily on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once daily on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once daily on days 1 to 4, 9 to 12
Supportive medications:
- Aspirin prophylaxis to decrease risk of DVTs
- Prophylactic "treatment with antiviral and antibiotic medications"
21-day cycles x 3-4 cycles
Regimen #3, Rosiñol, et al. 2012 (PETHEMA/GEM)
2012: Phase III Improved PFS Increased toxicity
- Bortezomib (Velcade) 1.3 mg/m2 once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 14 of cycle 1; Thalidomide (Thalomid) 100 mg PO once per day on days 15 to 28 of cycle 1; Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 28 of cycle 2 and thereafter
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
28-day cycles x 6 cycles
Supportive Medications:
- Low molecular weight heparin (LMWH) or aspirin recommended
References
- 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. link to original article contains protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
VTD-PACE
VTD-PACE: Velcade, Thalidomide, Dexamethasone, Platinum (cisplatin), Adriamycin (doxorubicin), Cyclophosphamide, Etoposide
Regimen, Barlogie, et al. 2007 (Total Therapy 3)
Level of Evidence: Prospective
Induction therapy
- Bortezomib (Velcade) 1.0 mg/m2 SC once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 200 mg PO once per day on days 4 to 7
- Dexamethasone (Decadron) 40 mg PO once per day on days 4 to 7
- Cisplatin (Platinol) 10 mg/m2/day (total dose per cycle: 40 mg/m2) IV continuous infusion over 4 days on days 4 to 7
- Doxorubicin (Adriamycin) 10 mg/m2/day (total dose per cycle: 40 mg/m2) IV continuous infusion over 4 days on days 4 to 7
- Cyclophosphamide (Cytoxan) 400 mg/m2/day (total dose per cycle: 1600 mg/m2) IV continuous infusion over 4 days on days 4 to 7
- Etoposide (Vepesid) 40 mg/m2/day (total dose per cycle: 160 mg/m2) IV continuous infusion over 4 days on days 4 to 7
- 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 106/kg. 87% of collections yielded at least 20 x 106/kg.
Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart
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 109/L:
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 21
21-day cycles, given between induction cycles and transplant
In other words, the initial therapy consists of: Induction therapy cycle 1, dexamethasone & thalidomide, induction therapy cycle 2, dexamethasone & thalidomide, then transplant.
Supportive medications, 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.
- Filgrastim (Neupogen) "was administered to support induction and consolidation chemotherapy regimens"
- "Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
- Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide
Autologous stem cell transplant
Full details were not provided in Barlogie, et al. 2007. Tandem autologous transplants were done between 2 to 6 months apart.
- Melphalan (Alkeran) 200 mg/m2
During the interim period after transplant 1 and transplant 2, patients receive:
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 21
21-day cycles, given in the time between and after each transplant; if platelets <50 x 109/L, proceed to year 1 of maintenance therapy. Otherwise, if platelets are at least 50 x 109/L, proceed to consolidation therapy.
Consolidation therapy
Cycle 1 of consolidation starts 1.5 to 4 months after the last transplant. Cycle 2 of consolidation starts 2-4 months after cycle 1 of consolidation.
- Bortezomib (Velcade) 1.0 mg/m2 SC once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
- Cisplatin (Platinol) 7.5 mg/m2/day (total dose per cycle: 30 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Doxorubicin (Adriamycin) 7.5 mg/m2/day (total dose per cycle: 30 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Cyclophosphamide (Cytoxan) 300 mg/m2/day (total dose per cycle: 1200 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Etoposide (Vepesid) 30 mg/m2/day (total dose per cycle: 120 mg/m2) IV continuous infusion over 4 days on days 1 to 4
2 cycles total are given according to the interval specified above, with the interim therapy below used
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 109/L:
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21
21-day cycles, given between consolidation cycles and maintenance
In other words, consolidation therapy consists of: Consolidation therapy cycle 1, dexamethasone & thalidomide, consolidation therapy cycle 2, dexamethasone & thalidomide, then maintenance therapy.
Supportive medications, 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.
- Filgrastim (Neupogen) "was administered to support induction and consolidation chemotherapy regimens"
- "Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
- Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide
Maintenance therapy, year 1 - VTD
Year 1 of maintenance therapy starts 1 to 4 months after consolidation cycle 2.
- Bortezomib (Velcade) 1.0 mg/m2 SC once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 8 to 11
28-day cycles x 1 year, then proceed to maintenance therapy years 2 to 3
Maintenance therapy, years 2 & 3 - TD
- Thalidomide (Thalomid) 100 mg PO once every other day
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
28-day cycles x 2 years
References
- 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. link to original article supportive medication details PubMed
- 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. link to original article contains verified protocol PubMed
- Kapoor P, Ramakrishnan V, Rajkumar SV. Bortezomib combination therapy in multiple myeloma. Semin Hematol. 2012 Jul;49(3):228-42. doi:10.1053/j.seminhematol.2012.04.010. Review. link to original article PubMed
VTP
VTP: Velcade (bortezomib), Thalidomide, Prednisone
Regimen
Level of Evidence: Phase III
Induction therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 15, then Thalidomide (Thalomid) 100 mg PO once per day on days 16 to 42
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
42-day cycle x 1 cycle, then
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
- Thalidomide (Thalomid) 100 mg PO once per day
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
35-day cycles x 5 cycles, then
Maintenance therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Only one of the following:
- Prednisone (Sterapred) 50 mg PO once every other day
- Thalidomide (Thalomid) 50 mg PO once per day
3-month cycles x up to 3 years
Supportive medications:
- "Patients with bone disease received bisphosphonates, and prophylactic aciclovir was recommended."
- Patients receiving thalidomide needed to have thromboprophylaxis with either aspirin or low-molecular-weight heparin
References
- 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. link to original article contains verified protocol PubMed
Post-transplant maintenance/consolidation
Bortezomib (Velcade)
Regimen #1, Mellqvist, et al. 2013
Level of Evidence: Phase III
This trial only included bortezomib-naive patients
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
Beginning 3 months after ASCT, 21-day cycles x 2 cycles, then
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles x 4 cycles
Supportive medications:
- "Bisphosphonates were administered according to national guidelines."
Regimen #2, Broyl, et al. 2010 & Sonneveld, et al. 2012 (HOVON-65/GMMG-HD4)
Level of Evidence: Phase III
- Bortezomib (Velcade) 1.3 mg/m2 IV once every two weeks x 2 years, starting 4 weeks after autologous stem cell transplant
References
- Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. Epub 2010 Sep 21. link to original article contains verified protocol PubMed
- 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. doi: 10.1200/JCO.2011.39.6820. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
- 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. doi: 10.1182/blood-2012-11 to 464503. Epub 2013 Apr 24. link to original article contains verified protocol PubMed
DCEP
DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol
Regimen
Level of Evidence: Phase III
Induction
See details under VD (velcade) or VAD (Vincristine), VAD-P
Consolidation
- Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
- Cyclophosphamide (Cytoxan) 400 mg/m2/day (total dose per cycle: 1600 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Etoposide (Vepesid) 40 mg/m2/day (total dose per cycle: 160 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Cisplatin (Platinol) 15 mg/m2/day (total dose per cycle: 60 mg/m2) IV continuous infusion over 4 days on days 1 to 4
28-day cycles x 2 cycles
References
- 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. link to original article contains verified protocol PubMed
Lenalidomide (Revlimid)
Regimen #1, Attal, et al. 2012
Level of Evidence: Phase III
Consolidation
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles x 2 cycles, then
Maintenance therapy
- Lenalidomide (Revlimid) 10 mg PO once per day x 3 months, then increased to 15 mg PO once per day if tolerated
given until progression of disease or unacceptable toxicity, or patient choice
Supportive medications:
- "Thromboprophylaxis was not used"
Regimen #2, McCarthy, et al. 2012
Level of Evidence: Phase III
Patients started therapy 100 to 120 days after autologous hematopoietic cell transplant (AHCT).
- 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 75,000/uL
- Dose adjustments can be found in the paper's supplementary appendix
given until progression of disease or unacceptable toxicity
Supportive medications:
- Patients at high risk of deep venous thrombosis (DVT) or pulmonary embolism (PE) received aspirin, 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 ≥ 2, smoking history, use of oral contraceptives, and[/or] concurrent use of epoetin."
Regimen #3, Palumbo, et al. 2010
Level of Evidence: Phase II
See First-line regimens: VDD; PAD: Palumbo, et al. 2010 for details about the induction therapy portion of this regimen.
Consolidation
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Prednisone (Sterapred) 50 mg PO once every other day
28-day cycles x 4 cycles, then proceed to maintenance therapy
Maintenance
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycles, given until relapsed disease
Supportive medications:
- Aspirin 100 mg PO once per day during lenalidomide treatment
References
- 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. link to original article contains verified protocol PubMed
- 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. doi: 10.1056/NEJMoa1114083. link to original article link to supplementary appendix contains verified protocol PubMed
- 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. link to original article contains verified protocol PubMed
- 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. link to original article contains protocol PubMed
Prednisone (Sterapred)
Regimen #1, Berenson, et al. 2002 (SWOG 9210)
Level of Evidence: Phase III
Preceded by VAD-P or VAD-P/Q
Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were then started on maintenance therapy:
- Prednisone (Sterapred) 50 mg PO once every other day until disease progression
Regimen #2, Berenson, et al. 2002 (SWOG 9210)
Level of Evidence: Phase III
Preceded by VAD-P or VAD-P/Q
Patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy were then started on maintenance therapy:
- Prednisone (Sterapred) 10 mg PO once every other day until disease progression
References
- 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. link to original article contains protocol PubMed
Thalidomide (Thalomid)
Regimen #1, Abdelkefi, et al. 2007
Level of Evidence: Phase III
- Thalidomide (Thalomid) 100 mg PO once daily x 6 months, starting 3 months after autologous stem cell transplant
Regimen #2, Broyl, et al. 2010 & Sonneveld, et al. 2012 (HOVON-65/GMMG-HD4)
Level of Evidence: Phase III
- Thalidomide (Thalomid) 50 mg PO once per day x 2 years, starting 4 weeks after autologous stem cell transplant
References
- 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. link to original article contains verified protocol PubMed
- Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, el Jarari L, Bertsch U, Lokhorst HM, Durie BG, Goldschmidt H, Sonneveld P. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. Epub 2010 Sep 21. link to original article contains verified protocol PubMed
- 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. doi: 10.1200/JCO.2011.39.6820. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
Thalidomide & Prednisone
Regimen, Stewart et al. 2013 (NCICCTG Myeloma 10 Trial)
Phase III Improved PFS Decreased QOL
- Thalidomide (Thalomid) 200 mg PO once per day
- Prednisone (Sterapred) 50 mg PO once every other day
Begin after autologous transplant and give for four years or until disease progression
Supportive Medications:
- "Bisphosphonates, histamine-2 blockers, and laxatives were recommended"
- "Anticoagulant and antiplatelet medications were not mandated"
References
- 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. doi: 10.1182/blood-2012-09-451872. Epub 2013 Jan 7. link to original article contains verified protocol PubMed
VTD
VTD: Velcade (bortezomib), Thalidomide, Dexamethasone
Regimen #1, Cavo, et al. 2010 & Cavo, et al. 2012 (GIMEMA)
2012: Phase III Improved PFS Increased toxicity
Induction therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 14 of cycle 1; Thalidomide (Thalomid) 200 mg PO once per day on days 15 to 21 of cycle 1; then Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 21 of cycles 2 & 3
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
21-day cycles x 3 cycles, then proceed to first stem cell transplant
First stem cell transplant
- Melphalan (Alkeran) 200 mg/m2 once on day -2
- Autologous stem cell rescue
Wait until count recovery, then proceed to thalidomide & dexamethasone therapy
Thalidomide & dexamethasone therapy
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles for 3 to 6 months, then proceed to second stem cell transplant
Second stem cell transplant
- Melphalan (Alkeran) 200 mg/m2 once on day -2
- Autologous stem cell rescue
Wait until 3 months after second transplant, then proceed to bortezomib, thalidomide, dexamethasone therapy
Bortezomib, thalidomide, dexamethasone therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 35
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
35-day cycles x 2 cycles, then proceed to dexamethasone maintenance therapy
Dexamethasone maintenance therapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles until progression, relapse, or undue toxicity
Supportive medications:
- Acyclovir (Zovirax) prophylaxis recommended
Regimen #2, Ladetto, et al. 2010
Level of Evidence: Phase II
Patients in Ladetto, et al. 2010 had at least a very good partial response (VGPR) after autologous stem cell transplantation.
- Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22
- 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
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
35-day cycles x 4 cycles
References
- 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. doi: 10.1200/JCO.2009.23.7172. Epub 2010 Mar 22. link to original article contains verified protocol PubMed
- 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. link to original article contains protocol PubMed
- 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. link to original article contains verified protocol PubMed
Relapsed/refractory
BD, Bort-Dex
BD: Bortezomib, Dexamethasone
Bort-Dex: Bortezomib, Dexamethasone
Regimen #1, Fukushima, et al. 2011 (BD)
Level of Evidence: Phase II
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
- Dexamethasone (Decadron) 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
35-day cycles, to be continued until complete response, progression of disease, or severe adverse events
Regimen #2, Hjorth, et al. 2012; Dimopoulos, et al. 2013
Level of Evidence: Phase III
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycles, to be continued until progression or best response, which would then be followed by 1 to 2 additional cycles
Supportive medications:
- "Antithrombotic prophylaxis and acyclovir prophylaxis were not mandatory according to the study protocol but used routinely in an increasing proportion of participating centers during the study period."
References
- Fukushima T, Nakamura T, Iwao H, Nakajima A, Miki M, Sato T, Sakai T, Sawaki T, Fujita Y, Tanaka M, Masaki Y, Nakajima H, Motoo Y, Umehara H. Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Anticancer Res. 2011 Jun;31(6):2297-302. link to original article contains verified protocol PubMed
- Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group (NMSG). Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. doi: 10.1111/j.1600-0609.2012.01775.x. Epub 2012 Mar 30. link to original article contains verified protocol PubMed
- Dimopoulos MA, Beksac M, Benboubker L, Roddie H, Allietta N, Broer E, Couturier C, Mazier MA, Angermund R, Facon T. Phase 2 study of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide for sub-optimal response as second-line treatment for patients with multiple myeloma. Haematologica. 2013 May 28. [Epub ahead of print] link to original article contains verified protocol PubMed
Bortezomib (Velcade)
Regimen #1, Richardson, et al. 2003, Richardson, et al. 2005, Richardson, et al. 2007 (APEX)
Level of Evidence: Phase III
Richardson, et al. 2003 only described the first 8 cycles of treatment
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
21-day cycles x 8 cycles, then
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
35-day cycles x 3 cycles
Supportive medications (described in Richardson, et al. 2005):
- Bisphosphonate IV therapy once every 3 to 4 weeks unless contraindicated
Regimen #2, Moreau, et al. 2011 (Subcutaneous vs. intravenous Bortezomib (Velcade) +/- Dexamethasone)
Level of Evidence: Phase III
- Bortezomib (Velcade) 1.3 mg/m2 SC/IV once per day on days 1, 4, 8, 11
- Subcutaneous injections are 2.5 mg/mL (3.5 mg bortezomib reconstituted in 1.4 mL NS)
- SC injections are in the thighs or abdomen, with injection sites rotated between proximal/distal right/left thigh and upper/lower right/left abdominal quadrants
- IV injections are 1 mg/mL (3.5 mg bortezomib reconstituted in 3.5 mL NS), given IV push over 3-5 seconds
- Patients with suboptimal response after cycle 4 (less than complete response (CR), without disease progression) could also receive, in addition to bortezomib: Dexamethasone (Decadron) 20 mg PO once daily on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycles x 8 to 10 cycles
Supportive medications:
- Bisphosphonates "according to established guidelines"
References
- Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. link to original article contains verified protocol PubMed
- Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. link to original article contains verified protocol PubMed
- Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. link to original article contains verified protocol PubMed
- Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431 to 40. Epub 2011 Apr 18. link to original article contains verified protocol PubMed
- Update: Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. doi: 10.3324/haematol.2012.067793. Epub 2012 Jun 11. link to original article PubMed
Bortezomib, Dexamethasone & Panobinostat
Regimen, Richardson, et al. 2013 (PANORAMA 2)
Level of Evidence: Phase II
Phase 1
- Bortezomib (Velcade) 1.3 mg/m2 IV twice per week
- Dexamethasone (Decadron) 20 mg PO four times per week (day of and day after bortezomib)
- Panobinostat (LBH589) 20mg PO three times per week
2-weeks on, 1-week off x 8 cycles
Phase 2
- Bortezomib (Velcade) 1.3 mg/m2 IV once per week on weeks 1, 2, 4, 5
- Dexamethasone (Decadron) 20 mg PO twice per week on weeks 1, 2, 4, 5 (day of and day after bortezomib)
- Panobinostat (LBH589) 20mg PO three times per week on weeks 1, 2, 4, 5
6-week cycles until progression, death, or excess toxicity
References
- Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, Mukhopadhyay S, Ondovik MS, Khan M, Paley CS, Lonial S. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013 Aug 15. [Epub ahead of print] link to original article Contains verified protocol PubMed
Bortezomib & Doxorubicin liposomal
Regimen
Level of Evidence: Phase III
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
- Doxorubicin liposomal (Doxil) 30 mg/m2 IV over at least 1 hour once on day 4, given after bortezomib
21-day cycles x up to 8 cycles, given until progression of disease, or unacceptable toxicity; treatment could be continued beyond 8 cycles if it was tolerated
Supportive medications:
- "Bisphosphonates were used according to established guidelines"
References
- Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article contains verified protocol PubMed
BLD
BLD: Bendamustine, Lenalidomide, Dexamethasone
Level of Evidence: 2012 Phase II
Regimen
This study involved dose escalation. Dosages listed are the determined maximally tolerated doses (MTD).
- Bendamustine (Treanda) 75 mg/m2 IV once per day on days 1 & 2
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg (no route specified) once per week
28-day cycles x up to 8 cycles
Supportive medications:
- Aspirin 325 mg PO once per day
- "Gastroprotectant" (H2-blocker or PPI)
References
- Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012 May 17;119(20):4608-13. doi: 10.1182/blood-2011-12-395715. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
Carfilzomib (Kyprolis)
Level of Evidence: 2012 Phase II
Regimen
- Carfilzomib (Kyprolis) 20 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1 to 2, 8 to 9, 15 to 16 of cycle 1; then on subsequent cycles, Carfilzomib (Kyprolis) 27 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1 to 2, 8 to 9, 15 to 16
- Note: Neither Vij, et al. 2012 nor Siegel, et al. 2012 specify that carfilzomib is capped at a body surface area of 2.2 m2, but the Carfilzomib (Kyprolis) package insert specifies that: "The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%."
28-week cycles x up to 12 cycles, given until progression of disease or unacceptable toxicity
Supportive medications:
- Dexamethasone (Decadron) 4 mg PO/IV before all doses in cycle 1 (Vij, et al. 2012 also administered one dose of dexamethasone 4 mg before the first increased dose of carfilzomib 27 mg/m2). Restart dexamethasone premedication if patients experience infusion reactions: "fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina."
- "All patients were to receive oral and intravenous fluids before dosing to assure adequate hydration."
Dose Adjustments:
- "Carfilzomib was withheld for grade 3 or 4 hematologic or nonhematologic toxicities and resumed at reduced doses of 15 mg/m2 in cycle 1 or 20 mg/m2 in cycle 2 and above on resolution."
References
- Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012 Jun 14;119(24):5661-70. Epub 2012 May 3. link to original article contains verified protocol PubMed
- Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. Epub 2012 Jul 25. link to original article contains verified protocol PubMed Pivotal trial for accelerated FDA approval
- Carfilzomib (Kyprolis) package insert
DCEP
DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol
Regimen
Level of Evidence: Phase II, <20 patients reported
These limited details are based on the abstract's description only. Full article was not available for review.
- Dexamethasone (Decadron) 40 mg IV bolus once per day on days 1 to 4
- Cyclophosphamide (Cytoxan) 400 mg/m2/day (total dose per cycle: 1600 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Etoposide (Vepesid) 40 mg/m2/day (total dose per cycle: 160 mg/m2) IV continuous infusion over 4 days on days 1 to 4
- Cisplatin (Platinol) 15 mg/m2/day (total dose per cycle: 60 mg/m2) IV continuous infusion over 4 days on days 1 to 4
28-day cycles
Supportive medications:
- G-CSF SC once per day, starting on day 5, to continue until neutrophil recovery
References
- Dadacaridou M, Papanicolaou X, Maltesas D, Megalakaki C, Patos P, Panteli K, Repousis P, Mitsouli-Mentzikof C. Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients. J BUON. 2007 Jan-Mar;12(1):41 to 4. PubMed
Dexamethasone (Decadron)
Regimen, Miguel, et al. 2013 (MM-003)
Level of Evidence: Phase III
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
28-day cycles, given until disease progression or unacceptable toxicity
References
- Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Sep 2. pii: S1470-2045(13)70380-2. doi: 10.1016/S1470-2045(13)70380-2. [Epub ahead of print] link to original article contains verified protocol PubMed
PD
PD: Pomalidomide, Dexamethasone
Regimen, Leleu, et al. 2013 (IFM 2009-02) & Miguel, et al. 2013 (MM-003)
Level of Evidence: Phase III
- Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per day on day 1, 8, 15, 22
28-day cycles, given until disease progression or unacceptable toxicity
Supportive medications:
- Miguel, et al. 2013: Thromboprohpylaxis required. "Choice of thromboprophylaxis and use of myeloid and erythroid growth factors was left to the physician's discretion."
- Leleu, et al. 2013: Thromboprophylaxis "at the physician's discretion"
- Leleu, et al. 2013: G-CSF allowed beginning with cycle 2 and on
References
- Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 2009-02. 2013 Mar 14;121(11):1968-1975. Epub 2013 Jan 14. link to original article contains verified protocol PubMed
- Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Sep 2. pii: S1470-2045(13)70380-2. doi: 10.1016/S1470-2045(13)70380-2. [Epub ahead of print] link to original article contains verified protocol PubMed
RD
RD: Revlimid, Dexamethasone
Regimen, Dimopoulos, et al. 2007; Weber, et al. 2007
Level of Evidence: Phase III
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 of cycles 1 to 4; Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of cycle 5 and thereafter
28-day cycles
References
- Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. link to original article contains verified protocol PubMed
- Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007 Nov 22;357(21):2133-42. link to original article contains verified protocol PubMed
Thal-Dex
Thal-Dex: Thalidomide, Dexamethasone
Regimen, Hjorth, et al. 2012
Level of Evidence: Phase III
- Thalidomide (Thalomid) 50 mg PO once per day, increased by 50 mg every 3 weeks to a maximum of 200 mg PO once per day "unless sufficient response was achieved by a lower dose"
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
21-day cycles, to be continued until progression or best response, which would then be followed by 1 to 2 additional cycles
Supportive medications:
- "Antithrombotic prophylaxis and acyclovir prophylaxis were not mandatory according to the study protocol but used routinely in an increasing proportion of participating centers during the study period."
References
- Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group (NMSG). Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. doi: 10.1111/j.1600-0609.2012.01775.x. Epub 2012 Mar 30. link to original article contains verified protocol PubMed
VMPT
VMPT: Velcade, Melphalan, Prednisone, Thalidomide
Regimen, Palumbo, et al. 2007
Level of Evidence: Phase II
- Bortezomib (Velcade) 1.0 to 1.3 mg/m2 IV bolus once per day on days 1, 4, 15, 22
- Melphalan (Alkeran) 6 mg/m2 PO once per day on days 1 to 5
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
- Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 35
35-day cycles x 6 cycles
References
- Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie Ematologicche dell'Adulto. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood. 2007 Apr 1;109(7):2767-72. link to original article contains protocol PubMed
Response criteria
Make note of these errors which remain in the online version as of 7/7/2013.
- International uniform response criteria (e.g. CR, sCR, VGPR, PR, SD) for multiple myeloma. (Leukemia 2006).[1]
- Disease progression criteria.[1]
Staging
External links
References
- ↑ 1.0 1.1 Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV; International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006 Sep;20(9):1467-73. Epub 2006 Jul 20. link to original article PubMed
- ↑ Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J. International staging system for multiple myeloma. J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4. link to original article PubMed
- ↑ Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9. doi: 10.1038/leu.2008.291. Epub 2008 Oct 30. link to original article PubMed
- ↑ Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54. PubMed