Light-chain (AL) amyloidosis
Page editor | Section editor | ||
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Samuel M. Rubinstein, MD University of North Carolina Chapel Hill, NC rubinstein_md |
Andrew J. Cowan, MD University of Washington Seattle, WA andrewcowanmd |
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25 regimens on this page
48 variants on this page
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Guidelines
BSH
- 2014: Wechalekar et al. Guidelines on the management of AL amyloidosis PubMed
EMN
- 2018: Gavriatopoulou et al. European myeloma network recommendations on diagnosis and management of patients with rare plasma cell dyscrasias PubMed
NCCN
First-line therapy (including transplant ineligible)
CRd
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CRd: Cyclophosphamide, Revlimid (Lenalidomide), low-dose dexamethasone
LDC: Lenalidomide, Dexamethasone, Cyclophosphamide
RdC: Revlimid (Lenalidomide), low-dose dexamethasone, Cyclophosphamide
Regimen variant #1, "LDC"
Study | Years of enrollment | Evidence |
---|---|---|
Cibeira et al. 2015 (LENDEXAL) | 2010-2012 | Phase 2 |
Chemotherapy
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 6: 300 mg/m2 IV once per day on days 1 & 8
- Cycles 7 to 12: 300 mg/m2 IV once on day 1
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 6: 20 mg PO once per day on days 1 to 4, 9 to 12
- Cycles 7 to 12: 20 mg PO once per day on days 1 to 4
- Cardiac stage III (this is not defined): upfront modification "allowed" but not defined
Targeted therapy
- Lenalidomide (Revlimid) by the following laboratory-based criteria:
- Normal eGFR: 15 mg PO once per day on days 1 to 21
- eGFR greater than 30 mL/min/1.73m2 but less than 50 mL/min/1.73m2: 10 mg PO once per day on days 1 to 21
- eGFR less than 30 mL/min/1.73m2: 5 mg PO once per day on days 1 to 21
Supportive medications
- Aspirin 100 mg PO once per day, or Low molecular weight heparin
28-day cycle for 12 cycles
Subsequent treatment
- Patients without progression who were tolerating therapy: Rd maintenance
Regimen variant #2, "CRd"
Study | Years of enrollment | Evidence |
---|---|---|
Kumar et al. 2012 (MC0685) | 2007-2008 | Phase 2 |
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
Targeted therapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
Supportive medications
- Thromboprophylaxis by the following criteria:
- Standard patients: Aspirin 81 to 325 mg PO once per day
- Patients with previous thrombotic histories or who were considered to be higher thrombotic risks: low molecular weight heparin or Warfarin (Coumadin)
- "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."
28-day cycle for up to 26 cycles (2 years)
Regimen variant #3, "RdC"
Study | Years of enrollment | Evidence |
---|---|---|
Kastritis et al. 2012 (RV-178) | 2008-2011 | Phase 1/2 |
This was the highest dose level tested in RV-178, which had no dose-limiting toxicities.
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg PO once per day on days 1 to 10
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
Targeted therapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
Supportive medications
- Thromboprophylaxis: Aspirin 100 mg PO once per day
- Proton pump inhibitor
- Trimethoprim-sulfamethoxazole (Bactrim), dose and schedule not listed
- Valacyclovir (Valtrex), dose and schedule not listed
28-day cycle for 12 cycles
References
- MC0685: Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. link to original article contains verified protocol link to PMC article PubMed NCT00564889
- RV-178: Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. link to original article contains verified protocol PubMed NCT00981708
- LENDEXAL: Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. link to original article contains verified protocol PubMed NCT01194791
CTD
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CTD: Cyclophosphamide, Thalidomide, Dexamethasone
Regimen variant #1
Study | Years of enrollment | Evidence |
---|---|---|
Wechalekar et al. 2007 | 2000-2005 | Phase 2 |
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
Targeted therapy
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day if well tolerated after 4 weeks
Supportive medications
- "Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis
21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response
Regimen variant #2, risk attenuated regimen
Study | Years of enrollment | Evidence |
---|---|---|
Wechalekar et al. 2007 | 2000-2005 | Phase 2 |
For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 15 to 18
Targeted therapy
- Thalidomide (Thalomid) as follows:
- Cycle 1: 50 mg PO once per day
- Cycle 2 (if tolerated): 100 mg PO once per day
- Cycle 3 (if tolerated): 150 mg PO once per day
- Cycle 4 onwards (if tolerated): 200 mg PO once per day
Supportive medications
- "Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis
28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response
References
- Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. link to original article contains verified protocol PubMed
Dara-CyBorD
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Dara-CyBorD: Daratumumab and hyaluronidase, Cyclophosphamide, Bortezomib, Dexamethasone
D-VCd: Daratumumab and hyaluronidase, Velcade (Bortezomib), Cyclophosphamide, low-dose dexamethasone
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kastritis et al. 2021 (ANDROMEDA) | 2018-2019 | Phase 3 (E-RT-esc) | CyBorD | Superior CHR 53.3% vs 18.1% (RR 2.9, 95% CI 2.1-4.1) |
Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.
Targeted therapy
- Daratumumab and hyaluronidase (Darzalex Faspro) as follows:
- Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15
- Cycle 7 onwards: 1800 mg SC once on day 1
- Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 8, 15, 22
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22
- Dexamethasone (Decadron) 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)
28-day cycle for 6 cycles
Subsequent treatment
- Daratumumab maintenance x 2 years
References
- ANDROMEDA: Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. link to original article contains verified protocol PubMed NCT03201965
Doxycycline-CyBorD
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Doxycycline-CyBorD: Doxycycline, Cyclophosphamide, Bortezomib, Dexamethasone
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Shen et al. 2021 (PUMCH-AL2017) | 2018-2019 | Randomized Phase 2 (E-esc) | CyBorD | Did not meet primary endpoint of cardiac PFS (HR 0.91, 95% CI 0.54-1.55) |
Targeted therapy
- Doxycycline 100 mg PO twice per day
- Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 8, 15, 22
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22
- Dexamethasone (Decadron) 40 mg PO or IV once per day on days 1, 8, 15, 22
28-day cycle for 9 cycles
References
- PUMCH-AL2017: Shen KN, Fu WJ, Wu Y, Dong YJ, Huang ZX, Wei YQ, Li CR, Sun CY, Chen Y, Miao HL, Zhang YL, Cao XX, Zhou DB, Li J. Doxycycline Combined With Bortezomib-Cyclophosphamide-Dexamethasone Chemotherapy for Newly Diagnosed Cardiac Light-Chain Amyloidosis: A Multicenter Randomized Controlled Trial. Circulation. 2021 Sep 10. link to original article contains verified protocol PubMed NCT03401372
Lenalidomide monotherapy
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Regimen variant #1, 15 mg dosing
Study | Years of enrollment | Evidence |
---|---|---|
Sanchorwala et al. 2006 | 2004-2006 | Phase 2 |
The trial used an initial dose of lenalidomide of 25 mg PO once per day, but it was reduced to 15 mg because 25 mg was poorly tolerated.
Targeted therapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
Supportive medications
- Aspirin 81 mg or 325 mg (physician discretion) PO once per day
28-day cycles
Subsequent treatment
- If no response after 3 cycles of therapy, then patients were escalated to lenalidomide & dexamethasone. Otherwise, treatment continued indefinitely
Regimen variant #2, 25 mg dosing
Study | Years of enrollment | Evidence |
---|---|---|
Dispenzieri et al. 2006 (MC0484) | 2004-2005 | Phase 2 |
Targeted therapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles
Subsequent treatment
- If no response after 3 cycles of therapy, then patients were escalated to lenalidomide & dexamethasone. Otherwise, treatment continued up to 12 cycles
References
- Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. link to original article contains verified protocol PubMed
- Update: Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC. Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis. Blood. 2010 Sep 16;116(11):1990-1. link to original article PubMed
- MC0484: Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. link to original article contains verified protocol PubMed
Melphalan & Dexamethasone
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M-DEX: Melphalan & DEXamethasone
Regimen variant #1, BSA-based melphalan
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jaccard et al. 2007 | 2000-2005 | Phase 3 (C) | High-dose melphalan, then auto HSCT | Seems to have superior OS |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Melphalan (Alkeran) 10 mg/m2 PO once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
Supportive medications
- Proton pump inhibitor
- Trimethoprim-Sulfamethoxazole (Bactrim DS) three times per week
1-month cycle for up to 18 cycles
Patients achieving complete hematologic remission could stop treatment after 12 cycles.
Regimen variant #2, weight-based melphalan
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Palladini et al. 2003 | 1999-2002 | Phase 2 | ||
Kastritis et al. 2020 (EMN-03) | 2011-2016 | Phase 3 (C) | BMDex | Inferior OS |
Chemotherapy
- Melphalan (Alkeran) 0.22 mg/kg PO once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
Supportive medications
- Omeprazole (Prilosec) 20 mg PO once per day on days 1 to 10
- Ciprofloxacin (Cipro) 250 mg PO twice per day on days 1 to 10
- Itraconazole (Sporanox) 100 mg PO once per day on days 1 to 10
28-day cycle for up to 9 cycles
References
- Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, Cavallero G, Rustichelli R, Virga G, Merlini G. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood. 2004 Apr 15;103(8):2936-8. Epub 2003 Dec 18. link to original article contains protocol PubMed
- Update: Palladini G, Russo P, Nuvolone M, Lavatelli F, Perfetti V, Obici L, Merlini G. Treatment with oral melphalan plus dexamethasone produces long-term remissions in AL amyloidosis. Blood. 2007 Jul 15;110(2):787-8. link to original article PubMed
- Update: Palladini G, Milani P, Foli A, Obici L, Lavatelli F, Nuvolone M, Caccialanza R, Perlini S, Merlini G. Oral melphalan and dexamethasone grants extended survival with minimal toxicity in AL amyloidosis: long-term results of a risk-adapted approach. Haematologica. 2014 Apr;99(4):743-50. Epub 2013 Nov 8. link to original article link to PMC article PubMed
- Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, Fermand JP; MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. link to original article contains verified protocol PubMed NCT00344526
- EMN-03: Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. link to original article contains verified protocol PubMed NCT01277016
MRD
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MRD: Melphalan, Revlimid (Lenalidomide), Dexamethasone
L-M-Dex: Lenalidomide, Melphalan, Dexamethasone
Regimen variant #1, "L-M-Dex"
Study | Years of enrollment | Evidence |
---|---|---|
Hegenbart et al. 2017 (LEOMEX) | 2009-2012 | Phase 2 |
Note: the manuscript states "treatment consisted of a total of 6 times 4 cycles"; this has been clarified with the authors to mean 6 times 4-week cycles.
Chemotherapy
- Melphalan (Alkeran) 0.15 mg/kg PO once per day on days 1 to 4
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
Targeted therapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycle for 6 cycles
Supportive medications
- Thromboprophylaxis with ONE of the following:
- Standard patients: Aspirin 100 mg PO once per day
- Patients with a history of VTE or thrombophilia: low-molecular weight heparin (dose/schedule not specified)
Regimen variant #2
Study | Years of enrollment | Evidence |
---|---|---|
Sanchorwala et al. 2012 (RV-AMYL-PI-0219) | 2008-2011 | Phase 2, <20 pts |
Sanchorawala et al. 2012 did not outright specify oral routes for melphalan and dexamethasone, but this is assumed based on how the paper discussed existing oral melphalan and dexamethasone regimens.
Chemotherapy
- Melphalan (Alkeran) 5 mg/m2 PO once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
Targeted therapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
Supportive medications
- Aspirin 325 mg PO once per day to decrease risk of Lenalidomide (Revlimid)-associated venous thromboembolism (VTE)
- Proton pump inhibitor to decrease risk of gastritis from Dexamethasone (Decadron)
28-day cycle for 12 cycles
Regimen variant #3
Study | Years of enrollment | Evidence |
---|---|---|
Moreau et al. 2010 (BRD 07/7-G) | 2008-2009 | Phase 1/2 |
This is the MTD dosing.
Chemotherapy
- Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
Targeted therapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
Supportive medications
28-day cycle for up to 9 cycles
References
- BRD 07/7-G: Moreau P, Jaccard A, Benboubker L, Royer B, Leleu X, Bridoux F, Salles G, Leblond V, Roussel M, Alakl M, Hermine O, Planche L, Harousseau JL, Fermand JP. Lenalidomide in combination with melphalan and dexamethasone in patients with newly diagnosed AL amyloidosis: a multicenter phase 1/2 dose-escalation study. Blood. 2010 Dec 2;116(23):4777-82. Epub 2010 Aug 19. link to original article contains verified protocol PubMed NCT00621400
- RV-AMYL-PI-0219: Sanchorawala V, Patel JM, Sloan JM, Shelton AC, Zeldis JB, Seldin DC. Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial. Haematologica. 2013 May;98(5):789-92. Epub 2012 Nov 9. link to original article contains verified protocol link to PMC article PubMed NCT00679367
- LEOMEX: Hegenbart U, Bochtler T, Benner A, Becker N, Kimmich C, Kristen AV, Beimler J, Hund E, Zorn M, Freiberger A, Gawlik M, Goldschmidt H, Hose D, Jauch A, Ho AD, Schönland SO. Lenalidomide/melphalan/dexamethasone in newly diagnosed patients with immunoglobulin light chain amyloidosis: results of a prospective phase 2 study with long-term follow up. Haematologica. 2017 Aug;102(8):1424-1431. Epub 2017 May 18. link to original article contains verified protocol link to PMC article PubMed NCT00883623
Bortezomib & Dexamethasone (VD)
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VD: Velcade (Bortezomib) & Dexamethasone
Regimen variant #1, lower-dose dex
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Sanchorawala et al. 2015 (X05292) | 2010-2013 | Phase 2 | HRR: 77% |
Minnema et al. 2019 (HOVON 104) | 2012-2016 | Phase 2 | HRR: 80% |
Targeted therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
Chemotherapy
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 4, 8, 11
Supportive medications
21-day cycle for 2 cycles
Subsequent treatment
Regimen variant #2, higher-dose dex
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Huang et al. 2014 (NJCT-0703) | 2009-2012 | Randomized Phase 2 (E-esc) | No induction | Seems to have superior OS |
Targeted therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 4, 8, 11
21-day cycle for 2 cycles
Subsequent treatment
References
- NJCT-0703: Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. link to original article contains verified protocol link to PMC article PubMed NCT01998503
- X05292: Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. link to original article contains verified protocol PubMed NCT01083316
- HOVON 104: Minnema MC, Nasserinejad K, Hazenberg B, Hegenbart U, Vlummens P, Ypma PF, Kröger N, Wu KL, Kersten MJ, Schaafsma MR, Croockewit S, de Waal E, Zweegman S, Tick L, Broijl A, Koene H, Bos G, Sonneveld P, Schönland S. Bortezomib-based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial. Haematologica. 2019 Nov;104(11):2274-2282. link to original article contains verified protocol link to PMC article PubMed NTR3220
VDC
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VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone
Regimen variant #1, 300/1.3/40, uncapped cyclophosphamide
Study | Evidence |
---|---|
Mikhael et al. 2012 | Retrospective |
Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.
Targeted therapy
- Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15, 22
Supportive medications
- Antiviral prophylaxis
28-day cycle for 2 to 6 cycles
Regimen variant #2, 300/1.3/40, capped cyclophosphamide
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kastritis et al. 2021 (ANDROMEDA) | 2018-2019 | Phase 3 (C) | Dara-CyBorD | Inferior CHR |
Note: the dexamethasone dose could be optionally reduced to 20 mg for patients who were older than 70, underweight, hypervolemic, with poorly controlled diabetes mellitus, or who had previous unacceptable side effects from corticosteroids.
Targeted therapy
- Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 8, 15, 22
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 (maximum dose of 500 mg) PO or IV once per day on days 1, 8, 15, 22
- Dexamethasone (Decadron) 40 mg PO or IV once per day on days 1, 8, 15, 22 (see note)
28-day cycle for 6 cycles
Regimen variant #3, 300/1.5/40
Study | Evidence |
---|---|
Mikhael et al. 2012 | Retrospective |
Note: Mikhael et al. 2012 does not explicitly define the route for bortezomib or dexamethasone; the routes below were used in the majority of patients, per the authors.
Targeted therapy
- Bortezomib (Velcade) 1.5 mg/m2 SC once per day on days 1, 8, 15, 22
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15, 22
Supportive medications
- Antiviral prophylaxis
28-day cycle for 2 to 6 cycles
References
- Retrospective: Mikhael JR, Schuster SR, Jimenez-Zepeda VH, Bello N, Spong J, Reeder CB, Stewart AK, Bergsagel PL, Fonseca R. Cyclophosphamide-bortezomib-dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL amyloidosis. Blood. 2012 May 10;119(19):4391-4. Epub 2012 Feb 13. link to original article contains verified protocol link to PMC article PubMed
- Retrospective: Jaccard A, Comenzo RL, Hari P, Hawkins PN, Roussel M, Morel P, Macro M, Pellegrin JL, Lazaro E, Mohty D, Mercie P, Decaux O, Gillmore J, Lavergne D, Bridoux F, Wechalekar AD, Venner CP. Efficacy of bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with high-risk cardiac AL amyloidosis (Mayo Clinic stage III). Haematologica. 2014 Sep;99(9):1479-85. Epub 2014 May 23. link to original article link to PMC article PubMed
- Retrospective: Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, Hawkins P, Merlini G, Wechalekar AD. A European collaborative study of cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL amyloidosis. Blood. 2015 Jul 30;126(5):612-5. Epub 2015 May 18. link to original article PubMed
- ANDROMEDA: Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, Sanchorawala V, Gibbs S, Mollee P, Venner CP, Lu J, Schönland S, Gatt ME, Suzuki K, Kim K, Cibeira MT, Beksac M, Libby E, Valent J, Hungria V, Wong SW, Rosenzweig M, Bumma N, Huart A, Dimopoulos MA, Bhutani D, Waxman AJ, Goodman SA, Zonder JA, Lam S, Song K, Hansen T, Manier S, Roeloffzen W, Jamroziak K, Kwok F, Shimazaki C, Kim JS, Crusoe E, Ahmadi T, Tran N, Qin X, Vasey SY, Tromp B, Schecter JM, Weiss BM, Zhuang SH, Vermeulen J, Merlini G, Comenzo RL; ANDROMEDA Trial Investigators. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. N Engl J Med. 2021 Jul 1;385(1):46-58. link to original article contains verified protocol PubMed NCT03201965
VMD
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VMD: Velcade (Bortezomib), Melphalan, Dexamethasone
BMDex: Bortezomib, Melphalan, Dexamethasone
Regimen variant #1, 8 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kastritis et al. 2020 (EMN-03) | 2011-2016 | Phase 3 (E-esc) | MDex | Superior OS |
Note: bortezomib administration was switched from IV to SC after the first 10 patients were enrolled in this arm.
Targeted therapy
- Bortezomib (Velcade) as follows:
- Cycles 1 & 2: 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
- Cycles 3 to 8: 1.3 mg/m2 SC once per day on days 1, 8, 15, 22
Chemotherapy
- Melphalan (Alkeran) 0.22 mg/kg PO once per day on days 1 to 4
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycle for 2 cycles, then 35-day cycle for 6 cycles
Regimen variant #2, 20 cycles
Study | Evidence |
---|---|
Zonder et al. 2009 | Phase 2 |
Note: this abstract is no longer available online.
Targeted therapy
- Bortezomib (Velcade) by the following symptom-based criteria, given first:
- No peripheral neuropathy at baseline: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
- Peripheral neuropathy at baseline: 1 mg/m2 IV once per day on days 1, 8, 15, 22
Chemotherapy
- Melphalan (Alkeran) by the following laboratory-based criteria, given third
- Serum creatinine up to 2.5 mg/dL: 9 mg/m2 PO once per day on days 1 to 4
- Serum creatinine greater than 2.5 mg/dL: 6 mg/m2 PO once per day on days 1 to 4
- Dexamethasone (Decadron) by the following age-based criteria, given second
- Patients up to 70 years old: 40 mg IV or PO once per day on days 1, 8, 15, 22
- Patients older than 70, with peripheral edema, or congestive heart failure (CHF): 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
4- to 6-week cycle for up to 20 cycles
References
- Abstract: Zonder JA, Sanchorawala V, Snyder RM, Matous J, Terebelo H, Janakiraman N, Mapara MY, Lalo S, Tageja N, Webb C, Monsma D, Sellers C, Abrams J, Gasparetto C. Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL Amyloidosis with Tolerable Neurotoxicity. Blood (ASH Annual Meeting Abstracts), Nov 2009; 114: 746. link to abstract
- EMN-03: Kastritis E, Leleu X, Arnulf B, Zamagni E, Cibeira MT, Kwok F, Mollee P, Hájek R, Moreau P, Jaccard A, Schönland SO, Filshie R, Nicolas-Virelizier E, Augustson B, Mateos MV, Wechalekar A, Hachulla E, Milani P, Dimopoulos MA, Fermand JP, Foli A, Gavriatopoulou M, Klersy C, Palumbo A, Sonneveld P, Johnsen HE, Merlini G, Palladini G. Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis. J Clin Oncol. 2020 Oct 1;38(28):3252-3260. Epub 2020 Jul 30. link to original article contains verified protocol PubMed NCT01277016
Consolidation after first-line therapy
Bortezomib & Melphalan, then auto HSCT
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Regimen variant #1, HDM 140 mg/m2
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Sanchorawala et al. 2015 (X05292) | 2010-2013 | Phase 2 | HRR: 77% |
Preceding treatment
Targeted therapy
- Bortezomib (Velcade) 1 mg/m2 IV once per day on days -6, -3, +1, +4
Chemotherapy
- Melphalan (Alkeran) 70 mg/m2 IV once per day on days -2 & -1
Stem cells re-infused on day 0
Regimen variant #2, HDM 200 mg/m2
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Sanchorawala et al. 2015 (X05292) | 2010-2013 | Phase 2 | HRR: 77% |
Preceding treatment
Targeted therapy
- Bortezomib (Velcade) 1 mg/m2 IV once per day on days -6, -3, +1, +4
Chemotherapy
- Melphalan (Alkeran) 100 mg/m2 IV once per day on days -2 & -1
Stem cells re-infused on day 0
References
- X05292: Sanchorawala V, Brauneis D, Shelton AC, Lo S, Sun F, Sloan JM, Quillen K, Seldin DC. Induction therapy with bortezomib followed by bortezomib-high dose melphalan and stem cell transplantation for light chain amyloidosis: Results of a prospective clinical trial. Biol Blood Marrow Transplant. 2015 Aug;21(8):1445-51. Epub 2015 Apr 6. link to original article contains verified protocol PubMed NCT01083316
Melphalan, then auto HSCT
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Regimen variant #1, 100 mg/m2
Study | Years of enrollment | Evidence |
---|---|---|
Landau et al. 2012 (NCT822) | 2007-2011 | Phase 2, <20 pts |
Note: this dose was intended for patients aged 61 to 70 with cardiac and/or renal compromise.
Chemotherapy
- Melphalan (Alkeran) 100 mg/m2 IV once (day not specified)
Stem cell re-infused on day not specified
Subsequent treatment
- Less than CR: BD consolidation x 6
Regimen variant #2, 140 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Skinner et al. 2004 | 1994-2002 | Case series | ||
Jaccard et al. 2007 | 2000-2005 | Phase 3 (E-esc) | M-DEX | Seems to have inferior OS |
Landau et al. 2012 (NCT822) | 2007-2011 | Phase 2, <20 pts | ||
Huang et al. 2014 (NJCT-0703) | 2009-2012 | Non-randomized portion of RCT |
Note: in Jaccard et al. 2007, this dose was intended for patients older than 65, with an EF below 30%, with a calculated CrCl of less than 30 ml per minute, or with severe liver disease. In NCT822, this dose was intended for patients up to age 60 with cardiac and/or renal compromise, or for patients aged 61 to 70 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 with cardiac or renal compromise.
Preceding treatment
- NJCT-0703: BD x 2 versus no induction
Chemotherapy
- Melphalan (Alkeran) 140 mg/m2 IV once on day 0
Stem cell re-infused on day 2
Subsequent treatment
- NCT822, less than CR: BD consolidation x 6
Regimen variant #3, 200 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Skinner et al. 2004 | 1994-2002 | Phase 2 | ||
Jaccard et al. 2007 | 2000-2005 | Phase 3 (E-esc) | M-DEX | Seems to have inferior OS |
Landau et al. 2012 (NCT822) | 2007-2011 | Phase 2, <20 pts | ||
Huang et al. 2014 (NJCT-0703) | 2009-2012 | Non-randomized portion of RCT |
Note: in NCT822, this dose was intended for patients up to age 60 without cardiac or renal compromise. In NJCT-0703, this dose was intended for patients up to age 65 without cardiac or renal compromise.
Preceding treatment
- NJCT-0703: BD x 2 versus no induction
Chemotherapy
- Melphalan (Alkeran) 200 mg/m2 IV once on day 0
Stem cell re-infused on day 2
Subsequent treatment
- NCT822, less than CR: BD consolidation x 6
References
- Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, Anderson JJ, O'Hara C, Finn KT, Libbey CA, Wiesman J, Quillen K, Swan N, Wright DG. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 2004 Jan 20;140(2):85-93. link to original article contains verified protocol PubMed
- Jaccard A, Moreau P, Leblond V, Leleu X, Benboubker L, Hermine O, Recher C, Asli B, Lioure B, Royer B, Jardin F, Bridoux F, Grosbois B, Jaubert J, Piette JC, Ronco P, Quet F, Cogne M, MAG; IFM. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. 2007 Sep 13;357(11):1083-93. link to original article contains verified protocol PubMed NCT00344526
- NCT822: Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. link to original article contains protocol PubMed
- NJCT-0703: Huang X, Wang Q, Chen W, Zeng C, Chen Z, Gong D, Zhang H, Liu Z. Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial. BMC Med. 2014 Jan 6;12:2. link to original article link to PMC article contains protocol PubMed NCT01998503
Bortezomib & Dexamethasone (VD)
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VD: Velcade (Bortezomib) & Dexamethasone
BD: Bortezomib & Dexamethasone
Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Landau et al. 2012 (NCT822) | 2007-2011 | Phase 2 |
Preceding treatment
- High-dose melphalan with autologous hematopoietic stem cell transplant, with less than CR
Targeted therapy
- Bortezomib (Velcade) as follows:
- Cycles 1 & 2: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Cycles 2 to 6: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
Chemotherapy
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
- Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
21-day cycle for 2 cycles, then 35-day cycle for 4 cycles (6 total)
References
- NCT822: Landau H, Hassoun H, Rosenzweig MA, Maurer M, Liu J, Flombaum C, Bello C, Hoover E, Riedel E, Giralt S, Comenzo RL. Bortezomib and dexamethasone consolidation following risk-adapted melphalan and stem cell transplantation for patients with newly diagnosed light-chain amyloidosis. Leukemia. 2013 Apr;27(4):823-8. Epub 2012 Sep 27. link to original article contains verified protocol PubMed
Maintenance after first-line therapy
Lenalidomide & Dexamethasone (Rd)
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Rd: Revlimid (Lenalidomide) & low-dose dexamethasone
RevDex: Revlimid (Lenalidomide) & Dexamethasone
Ld: Lenalidomide & low-dose dexamethasone
LenDex: Lenalidomide & Dexamethasone
Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Cibeira et al. 2015 (LENDEXAL) | 2010-2012 | Phase 2 |
Preceding treatment
- LDC x 12
Targeted therapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
Chemotherapy
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
Supportive medications
- Aspirin 100 mg PO once per day or Low molecular weight heparin
28-day cycle for 39 cycles (3 years)
References
- LENDEXAL: Cibeira MT, Oriol A, Lahuerta JJ, Mateos MV, de la Rubia J, Hernández MT, Granell M, Fernández de Larrea C, San Miguel JF, Bladé J; PETHEMA. A phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with systemic immunoglobulin light chain amyloidosis. Br J Haematol. 2015 Sep;170(6):804-13. Epub 2015 May 14. link to original article contains verified protocol PubMed NCT01194791
Relapsed or refractory
Bendamustine & Dexamethasone
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Lentzsch et al. 2020 (AAAJ7800) | 2013-2016 | Phase 2 |
Chemotherapy
- Bendamustine 100 mg/m2 IV once per day on days 1 & 2
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycle for up to 6 cycles or progression of disease
References
- AAAJ7800: Lentzsch S, Lagos GG, Comenzo RL, Zonder JA, Osman K, Pan S, Bhutani D, Pregja S, Sanchorawala V, Landau H. Bendamustine With Dexamethasone in Relapsed/Refractory Systemic Light-Chain Amyloidosis: Results of a Phase II Study. J Clin Oncol. 2020 May 1;38(13):1455-1462. Epub 2020 Feb 21 link to original article contains verified protocol link to PMC article PubMed NCT01222260
Bortezomib monotherapy
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Regimen variant #1, twice per week
Study | Years of enrollment | Evidence |
---|---|---|
Reece et al. 2011 (CAN2007) | 2005-2009 | Phase 2 |
Targeted therapy
- Bortezomib (Velcade) 1.3 mg/m2 (route not specified) once per day on days 1, 4, 8, 11
21-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit
Regimen variant #2, weekly schedule
Study | Years of enrollment | Evidence |
---|---|---|
Reece et al. 2011 (CAN2007) | 2005-2009 | Phase 2 |
Targeted therapy
- Bortezomib (Velcade) 1.6 mg/m2 (route not specified) once per day on days 1, 8, 15, 22
35-day cycle for up to 8 cycles, with extended treatment allowed for patients with clear clinical benefit
References
- CAN2007: Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Efficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic AL amyloidosis: results of a phase 1/2 study. Blood. 2011 Jul 28;118(4):865-73. Epub 2011 May 11. link to original article contains verified protocol PubMed NCT00298766
- Update: Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Kukreti V, Vescio RA, Pei L, Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL. Long-term follow-up from a phase 1/2 study of single-agent bortezomib in relapsed systemic AL amyloidosis. Blood. 2014 Oct 16;124(16):2498-506. Epub 2014 Sep 8. link to original article contains verified protocol link to PMC article PubMed
CRd
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CRd: Cyclophosphamide, Revlimid (Lenalidomide), low-dose dexamethasone
CLD: Cyclophosphamide, Lenalidomide Dexamethasone
RdC: Revlimid (Lenalidomide), low-dose dexamethasone, Cyclophosphamide
Regimen variant #1
Study | Years of enrollment | Evidence |
---|---|---|
Kumar et al. 2012 (MC0685) | 2007-2008 | Phase 2 |
Palladini et al. 2012 (AC-003-IT) | 2008-2009 | Phase 2 |
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
- In AC-003-IT only, patients who retained over 3% body weight despite "optimal diuretic use" received 20 mg PO once per day on days 1, 8, 15, 22
Targeted therapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
Supportive medications
(varies depending on reference)
- Thromboprophylaxis with one of the following:
- Standard patients: Aspirin 81 to 325 mg PO once per day
- In MC0685, patients with previous thrombotic histories or who were considered to be higher thrombotic risks were recommended to receive: low molecular weight heparin or Warfarin (Coumadin)
- MC0685: "Routine antibiotic, antiviral, or antifungal prophylaxis was not mandated and left to the discretion of the treating physician."
28-day cycle for up to 9 cycles or 2 years, depending on reference
Regimen variant #2
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Kastritis et al. 2012 (RV-178) | 2008-2011 | Phase 1/2 | ORR: 55% (hematologic response) 22% (organ response) |
This was the highest dose level tested, which had no dose-limiting toxicities.
Chemotherapy
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
- Cyclophosphamide (Cytoxan) 100 mg PO once per day on days 1 to 10
Targeted therapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
Supportive medications
- Thromboprophylaxis: Aspirin 100 mg PO once per day
- Proton pump inhibitor
- Trimethoprim-sulfamethoxazole (Bactrim), dose and schedule not listed
- Valacyclovir (Valtrex), dose and schedule not listed
28-day cycle for 12 cycles
References
- MC0685: Kumar SK, Hayman SR, Buadi FK, Roy V, Lacy MQ, Gertz MA, Allred J, Laumann KM, Bergsagel LP, Dingli D, Mikhael JR, Reeder CB, Stewart AK, Zeldenrust SR, Greipp PR, Lust JA, Fonseca R, Russell SJ, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide, and dexamethasone (CRd) for light-chain amyloidosis: long-term results from a phase 2 trial. Blood. 2012 May 24;119(21):4860-7. Epub 2012 Apr 13. link to original article contains verified protocol link to PMC article PubMed NCT00564889
- RV-178: Kastritis E, Terpos E, Roussou M, Gavriatopoulou M, Pamboukas C, Boletis I, Marinaki S, Apostolou T, Nikitas N, Gkortzolidis G, Michalis E, Delimpasi S, Dimopoulos MA. A phase 1/2 study of lenalidomide with low-dose oral cyclophosphamide and low-dose dexamethasone (RdC) in AL amyloidosis. Blood. 2012 Jun 7;119(23):5384-90. Epub 2012 Apr 18. link to original article contains verified protocol PubMed NCT00981708
- AC-003-IT: Palladini G, Russo P, Milani P, Foli A, Lavatelli F, Nuvolone M, Perlini S, Merlini G. A phase II trial of cyclophosphamide, lenalidomide and dexamethasone in previously treated patients with AL amyloidosis. Haematologica. 2013 Mar;98(3):433-6. Epub 2012 Sep 14. link to original article contains verified protocol link to PMC article PubMed NCT00607581
CTD
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CTD: Cyclophosphamide, Thalidomide, Dexamethasone
Regimen variant #1
Study | Years of enrollment | Evidence |
---|---|---|
Wechalekar et al. 2007 | 2000-2005 | Phase 2 |
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
Targeted therapy
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21, then increased to 200 mg PO once per day on days 1 to 21 if well tolerated after 4 weeks
Supportive medications
- "Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis
21-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response
Regimen variant #2, risk attenuated regimen
Study | Years of enrollment | Evidence |
---|---|---|
Wechalekar et al. 2007 | 2000-2005 | Phase 2 |
For elderly patients (age greater than 70 years), NYHA heart failure greater than class II, and those with significant fluid overload.
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 15 to 18
Targeted therapy
- Thalidomide (Thalomid) as follows:
- Cycle 1: 50 mg PO once per day
- Cycle 2 (if tolerated): 100 mg PO once per day
- Cycle 3 (if tolerated): 150 mg PO once per day
- Cycle 4 onwards (if tolerated): 200 mg PO once per day
Supportive medications
- "Antimicrobial and thromboprophylaxis were given according to local protocol"; no routine thromboprophylaxis
28-day cycles, "given until a stable clonal response was achieved on consecutive samples at least 4 weeks apart" or until confirmed lack of response
References
- Wechalekar AD, Goodman HJ, Lachmann HJ, Offer M, Hawkins PN, Gillmore JD. Safety and efficacy of risk-adapted cyclophosphamide, thalidomide, and dexamethasone in systemic AL amyloidosis. Blood. 2007 Jan 15;109(2):457-64. Epub 2006 Sep 21. link to original article contains verified protocol PubMed
Cyclophosphamide & Dexamethasone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dispenzieri et al. 2021 (Tourmaline-AL1) | 2012-2018 | Phase 3 (C) | Ixazomib & Dexamethasone | Did not meet primary endpoint of HRR |
Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22
28-day cycles
References
- Tourmaline-AL1: Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. link to original article PubMed NCT01659658
Daratumumab monotherapy
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Regimen variant #1
Study | Evidence |
---|---|
Kaufman et al. 2017 | Retrospective |
Targeted therapy
- Daratumumab (Darzalex) as follows:
- Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
- Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15
- Cycle 5 onwards: 16 mg/kg IV once on day 1
Supportive medications
- Acetaminophen (Tylenol) 650 mg PO once, prior to daratumumab
- Diphenhydramine (Benadryl) 50 mg PO once, prior to daratumumab
- Dexamethasone (Decadron) 20 mg IV or PO once, prior to daratumumab
Continued indefinitely
Regimen variant #2
Study | Years of enrollment | Evidence |
---|---|---|
Roussel et al. 2020 (AMYDARA) | 2016-2018 | Phase 2 |
Targeted therapy
- Daratumumab (Darzalex) as follows:
- Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15
Supportive medications
- Acetaminophen (Tylenol) 650 mg PO once, prior to daratumumab
- Diphenhydramine (Benadryl) 50 mg PO once, prior to daratumumab
- Dexamethasone (Decadron) 20 mg IV or PO once, prior to daratumumab
Regimen variant #3
Study | Years of enrollment | Evidence |
---|---|---|
Sanchorawala et al. 2020 (H-35360) | 2017-2018 | Phase 2 |
Targeted therapy
- Daratumumab (Darzalex) as follows:
- Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
- Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15
Supportive medications
- Acetaminophen (Tylenol) 650 mg PO once, prior to daratumumab
- Diphenhydramine (Benadryl) 50 mg PO once, prior to daratumumab
- Dexamethasone (Decadron) 20 mg IV or PO once, prior to daratumumab
Continued indefinitely
References
- Retrospective: Kaufman GP, Schrier SL, Lafayette RA, Arai S, Witteles RM, Liedtke M. Daratumumab yields rapid and deep hematologic responses in patients with heavily pretreated AL amyloidosis. Blood. 2017 Aug 17;130(7):900-902. link to original article PubMed
- AMYDARA: Roussel M, Merlini G, Chevret S, Arnulf B, Stoppa AM, Perrot A, Palladini G, Karlin L, Royer B, Huart A, Macro M, Morel P, Frenzel L, Touzeau C, Boyle E, Dorvaux V, Le Bras F, Lavergne D, Bridoux F, Jaccard A. A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis. Blood. 2020 Apr 30;135(18):1531-1540. link to original article PubMed NCT02816476
- H-35360: Sanchorawala V, Sarosiek S, Schulman A, Mistark M, Migre ME, Cruz R, Sloan JM, Brauneis D, Shelton AC. Safety, tolerability, and response rates of daratumumab in relapsed AL amyloidosis: results of a phase 2 study. Blood. 2020 Apr 30;135(18):1541-1547. link to original article link to PMC article PubMed NCT02841033
Dexamethasone monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dispenzieri et al. 2021 (Tourmaline-AL1) | 2012-2018 | Phase 3 (C) | Ixazomib & Dexamethasone | Did not meet primary endpoint of HRR |
Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
28-day cycles
References
- Tourmaline-AL1: Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. link to original article PubMed NCT01659658
Ixazomib monotherapy
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Sanchorawala et al. 2017 (C16007) | 2012-NR | Phase 1/2 |
This is the MTD dosing determined in this phase 1/2 trial.
Targeted therapy
- Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
28-day cycle for up to 12 cycles or longer if patient was "deriving clinical benefit"
Subsequent treatment
- Patients with less than PR after four cycles: Ixazomib & dexamethasone
References
- C16007: Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. link to original article contains verified protocol PubMed NCT01318902
Ixazomib & Dexamethasone
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Sanchorawala et al. 2017 (C16007) | 2012-NR | Phase 1/2 |
Preceding treatment
- Ixazomib x 4, with less than PR
Targeted therapy
- Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles
References
- C16007: Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schönland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. Epub 2017 May 26. link to original article contains verified protocol PubMed NCT01318902
Melphalan & Dexamethasone
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dispenzieri et al. 2021 (Tourmaline-AL1) | 2012-2018 | Phase 3 (C) | Ixazomib & Dexamethasone | Did not meet primary endpoint of HRR |
Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Melphalan (Alkeran) 0.22 mg/kg PO once per day on days 1 to 4
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
28-day cycles
References
- Tourmaline-AL1: Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. link to original article PubMed NCT01659658
Pomalidomide & Dexamethasone (PD)
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Pd: Pomalidomide & low-dose dexamethasone
Regimen variant #1
Study | Years of enrollment | Evidence |
---|---|---|
Palladini et al. 2017 (AC-007-IT) | 2012-2013 | Phase 2 |
Targeted therapy
- Pomalidomide (Pomalyst) 4 mg PO once per day
Chemotherapy
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22
28-day cycles
Regimen variant #2
Study | Years of enrollment | Evidence |
---|---|---|
Sanchorawala et al. 2016 (PO-AMYL-PI-0024) | 2012-2015 | Phase 1/2, <20 pts |
Note: although the trial enrolled 27 patients, only 18 were treated at the MTD reproduced here:
Targeted therapy
- Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
Chemotherapy
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22
28-day cycles
Regimen variant #3
Study | Years of enrollment | Evidence |
---|---|---|
Dispenzieri et al. 2012 (MC0789) | 2008-2010 | Phase 2 |
Targeted therapy
- Pomalidomide (Pomalyst) 2 mg PO once per day
- See Dispenzieri et al. 2012 for dose escalations and reductions
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
Supportive medications
- Thromboprophylaxis: Aspirin 325 mg PO once per day
28-day cycles
References
- MC0789: Dispenzieri A, Buadi F, Laumann K, LaPlant B, Hayman SR, Kumar SK, Dingli D, Zeldenrust SR, Mikhael JR, Hall R, Rajkumar SV, Reeder C, Fonseca R, Bergsagel PL, Stewart AK, Roy V, Witzig TE, Lust JA, Russell SJ, Gertz MA, Lacy MQ. Activity of pomalidomide in patients with immunoglobulin light-chain amyloidosis. Blood. 2012 Jun 7;119(23):5397-404. Epub 2012 Apr 4. link to original article contains verified protocol link to PMC article PubMed NCT00558896
- PO-AMYL-PI-0024: Sanchorawala V, Shelton AC, Lo S, Varga C, Sloan JM, Seldin DC. Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial. Blood. 2016 Aug 25;128(8):1059-62. Epub 2016 Jul 5. link to original article contains verified protocol PubMed NCT01570387
- AC-007-IT: Palladini G, Milani P, Foli A, Basset M, Russo F, Perlini S, Merlini G. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017 Apr 13;129(15):2120-2123. Epub 2017 Jan 27. link to original article contains verified protocol PubMed NCT01510613
Lenalidomide & Dexamethasone (Rd)
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Rd: Revlimid (Lenalidomide) & low-dose dexamethasone
RevDex: Revlimid (Lenalidomide) & Dexamethasone
Ld: Lenalidomide & low-dose dexamethasone
LenDex: Lenalidomide & Dexamethasone
Regimen variant #1, weekly dexamethasone
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Palladini et al. 2012 | 2007-2009 | Phase 2 | ||
Dispenzieri et al. 2021 (Tourmaline-AL1) | 2012-2018 | Phase 3 (C) | Ixazomib & Dexamethasone | Did not meet primary endpoint of HRR |
Targeted therapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
Chemotherapy
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22
Supportive medications
- Thromboprophylaxis: Aspirin 100 mg PO once per day
- Omeprazole (Prilosec) 20 mg PO once per day
28-day cycles
Regimen variant #2, pulsed dexamethasone
Study | Years of enrollment | Evidence |
---|---|---|
Sanchorwala et al. 2006 | 2004-2006 | Phase 2 |
Preceding treatment
- Treatment failure after lenalidomide x 3 cycles
Targeted therapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
Chemotherapy
- Dexamethasone (Decadron) as follows:
- Odd cycles: 10 to 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
Supportive medications
- Thromboprophylaxis: Aspirin 81 or 325 mg PO once per day
- Proton pump inhibitor
28-day cycles
References
- Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, Skinner M, Seldin DC. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood. 2007 Jan 15;109(2):492-6. Epub 2006 Sep 7. link to original article contains verified protocol PubMed
- Palladini G, Russo P, Foli A, Milani P, Lavatelli F, Obici L, Nuvolone M, Brugnatelli S, Invernizzi R, Merlini G. Salvage therapy with lenalidomide and dexamethasone in patients with advanced AL amyloidosis refractory to melphalan, bortezomib, and thalidomide. Ann Hematol. 2012 Jan;91(1):89-92. link to original article contains verified protocol PubMed
- Tourmaline-AL1: Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. link to original article PubMed NCT01659658
Lenalidomide & Dexamethasone (RD)
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RD: Revlimid (Lenalidomide) & high-dose Dexamethasone
Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Dispenzieri et al. 2006 (MC0484) | 2004-2005 | Phase 2 |
Preceding treatment
- Treatment failure after lenalidomide x 3 cycles
Targeted therapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 15 to 18
28-day cycle for 12 or more cycles
References
- MC0484: Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, Lust JA, Allred JB, Witzig TE, Rajkumar SV, Greipp PR, Russell SJ, Kabat B, Gertz MA. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood. 2007 Jan 15;109(2):465-70. Epub 2006 Sep 28. link to original article contains verified protocol PubMed
Thalidomide & Dexamethasone (TD)
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dispenzieri et al. 2021 (Tourmaline-AL1) | 2012-2018 | Phase 3 (C) | Ixazomib & Dexamethasone | Did not meet primary endpoint of HRR |
Note: dosing is from ClinicalTrials.gov. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Thalidomide (Thalomid) 200 mg PO once per day
Chemotherapy
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22
28-day cycles
References
- Tourmaline-AL1: Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, Landau HJ, Kwok F, Suzuki K, Comenzo RL, Berg D, Liu G, Kumar A, Faller DV, Merlini G. A randomized phase 3 study of ixazomib-dexamethasone versus physician's choice in relapsed or refractory AL amyloidosis. Leukemia. 2021 Jun 24. Epub ahead of print. link to original article PubMed NCT01659658