Difference between revisions of "Multiple myeloma"
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# 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. [http://www.bloodjournal.org/content/119/24/5661.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22555973 PubMed] | # 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. [http://www.bloodjournal.org/content/119/24/5661.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22555973 PubMed] | ||
+ | # Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S, Wong AF, Wang M. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012 Sep;158(6):739-48. Epub 2012 Jul 30. [http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2012.09232.x/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22845873 PubMed] | ||
# Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. [http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(12)00148-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23040437 PubMed] | # Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. [http://www.clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(12)00148-6/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/23040437 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. [http://www.bloodjournal.org/content/120/14/2817.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22833546 PubMed] '''Pivotal trial for accelerated FDA approval''' | # 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. [http://www.bloodjournal.org/content/120/14/2817.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22833546 PubMed] '''Pivotal trial for accelerated FDA approval''' |
Revision as of 22:27, 23 November 2016
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Untreated (including transplant ineligible), randomized data
Note: most but not all multiple myeloma first-line regimens specify whether patients are transplant eligible, or not. The top-line inclusion criteria from each prospectively enrolling regimen are reported.
CPR
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CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)
Regimen
Study | Evidence | Comparator | Efficacy |
Magarotto et al. 2016 (EMN01) | Phase III | MPR | Might have inferior PFS |
Rd | Seems not superior |
This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years) or coexisting comorbidities. This is the dosing used after a mid-protocol amendment.
Chemotherapy
- Cyclophosphamide (Cytoxan) 50 mg PO once per day on days 1 to 21
- Prednisone (Sterapred) 25 mg PO once every other day
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
Supportive medications
- Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
28-day cycle for 9 cycles
Patients were then randomized to lenalidomide maintenance versus lenalidomide & prednisone maintenance.
References
- Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed
CTD
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CTD: Cyclophosphamide, Thalidomide, Dexamethasone
CTDa: Cyclophosphamide, Thalidomide, Dexamethasone, attenuated
Regimen #1, CTD
Study | Evidence | Comparator | Efficacy |
Morgan et al. 2011 (MRC Myeloma IX) | Phase III | CVAD | Not reported |
This is an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference.
Chemotherapy
- 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
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 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
21-day cycle for up to 6 cycles until maximum response
All responding patients proceeded to high-dose melphalan and autologous hematopoietic cell transplant.
Regimen #2, CTDa
Study | Evidence | Comparator | Efficacy |
Morgan et al. 2011 (MRC Myeloma IX) | Phase III | MP | Not reported |
This is a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference.
Chemotherapy
- 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
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
28-day cycle for 6 to 9 cycles
Patients were then randomized to thalidomide maintenance versus no further treatment.
References
- Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article contains verified protocol PubMed
- Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to PMC article contains verified protocol PubMed
- Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-Term Follow-Up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
CVAD
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CVAD: Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Morgan et al. 2011 (MRC Myeloma IX) | Phase III | CTD | Not reported |
This is an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference.
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
- Vincristine (Oncovin) 0.4 mg/day IV continuous infusion on days 1 to 4 (total dose per cycle: 1.6 mg)
- Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion on days 1 to 4 (total dose per cycle: 36 mg/m2)
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 12 to 15
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
21-day cycle for 4 to 6 cycles until maximum response
All responding patients proceeded to high-dose melphalan and autologous hematopoietic cell transplant.
References
- Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article contains verified protocol PubMed
- Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to PMC article contains protocol PubMed
- Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-Term Follow-Up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
Dexamethasone (Decadron)
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Rajkumar et al. 2008 | Phase III | TD | Inferior TTP |
This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.
Chemotherapy
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycle 5 onwards: 40 mg PO once per day on days 1 to 4
28-day cycles
Regimen #2
Study | Evidence | Comparator | Efficacy | Toxicity |
Rajkumar et al. 2005 | Phase III | TD | Seems to have inferior RR | Superior toxicity |
This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.
Chemotherapy
- Dexamethasone (Decadron) as follows:
- Odd-numbered cycles: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Even-numbered cycles: 40 mg PO once per day on days 1 to 4
28-day cycles
Regimen #3
Study | Evidence | Comparator | Efficacy |
Facon et al. 2005 (IFM 95-01) | Phase III | DEX-IFN | Seems not superior |
MP M-DEX |
Inferior PFS |
This regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details.
Chemotherapy
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycles 3 to 12: 40 mg PO once per day on days 1 to 4
6-week cycle for 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
- 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
- Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010 Dec 23;116(26):5838-41. Epub 2010 Sep 27. link to original article PubMed
DEX-IFN
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DEXamethasone, InterFeroN alfa-2b
Regimen
Study | Evidence | Comparator | Efficacy |
Facon et al. 2005 (IFM 95-01) | Phase III | Dexamethasone | Seems not superior |
MP M-DEX |
Inferior PFS |
This regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details.
Chemotherapy
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycles 3 to 12: 40 mg PO once per day on days 1 to 4
- 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 cycle for 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; VAD doxil
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DVD: Doxil (Liposomal Doxorubicin), Vincristine, Dexamethasone
DVd: Doxil (Liposomal Doxorubicin), Vincristine, low-dose dexamethasone
VAD doxil: Vincristine, Adriamycin liposomal (Doxil), Dexamethasone
Regimen #1, "DVd"
Study | Evidence | Comparator | Efficacy |
Rifkin et al. 2006 | Phase III | VAd | Non-inferior ORR |
This regimen was intended for patients ≥ 18 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria.
Chemotherapy
- 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 #2
Study | Evidence | Comparator | Efficacy |
Dimopoulos et al. 2003 | Phase III | VAD | Seems not superior |
Zervas et al. 2007 | Phase III | TVAD-Doxil | Seems to have inferior OS |
Dimopoulos et al. 2003 was open to all patients with previously untreated multiple myeloma who were considered candidates for systemic treatment. Zervas et al. 2007 was open to patients aged 18 to 75 years old with previously untreated symptomatic MM and a life expectancy of > 6 months.
Chemotherapy
- 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) as follows:
- Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycles 2 & 4: 40 mg PO once per day on days 1 to 4
Supportive medications (which were in the cited Segeren et al. 1999 VAD protocol 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"
4-week cycle for 4 cycles
References
- 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
M-DEX
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M-DEX: Melphalan, DEXamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Facon et al. 2005 (IFM 95-01) | Phase III | Dexamethasone DEX-IFN |
Superior PFS |
MP | Seems not superior |
This regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details.
Chemotherapy
- Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycles 3 to 12: 40 mg PO once per day on days 1 to 4
6-week cycle for 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 verified protocol PubMed
MP
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MP: Melphalan, Prednisone/rednisolone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2012 (MM-015) | Phase III | MPR | Seems not superior |
MPR-R | Inferior PFS |
This regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (≥65 years of age).
Chemotherapy
- 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
Supportive medications
- Aspirin 75 to 100 mg PO once per day as thromboprophylaxis
28-day cycle for 9 cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
Morgan et al. 2011 (MRC Myeloma IX) | Phase III | CTDa | Not reported |
This is a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference. Note that this regimen uses prednisolone, not prednisone.
Chemotherapy
- 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
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
28-day cycle for 6 to 9 cycles
Patients were then randomized to thalidomide maintenance versus no further treatment.
Regimen #3
Study | Evidence | Comparator | Efficacy |
Wijermans et al. 2010 (HOVON 49) | Phase III | MP-T | Might have inferior OS |
This regimen was intended for patients with previously untreated MM older than age 65 years.
Chemotherapy
- 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
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."
28-day cycle for 8 cycles
Regimen #4
Study | Evidence | Comparator | Efficacy |
Hulin et al. 2009 (IFM 01/01) | Phase III | MPT | Seems to have inferior OS |
This regimen was intended for patients who had stage II or III newly diagnosed multiple myeloma according to the Durie-Salmon criteria and were at least 75 years of age. Certain stage I patients were allowed; see text for details.
Chemotherapy
- 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 cycle for 12 cycles
Regimen #5
Study | Evidence | Comparator | Efficacy |
San Miguel et al. 2008 (VISTA) | Phase III | VMP | Inferior OS |
This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (≥65 years) or coexisting conditions.
Chemotherapy
- 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 cycle for 9 cycles
Regimen #6
Study | Evidence | Comparator | Efficacy |
Facon et al. 2005 (IFM 95-01) | Phase III | Dexamethasone DEX-IFN |
Superior PFS |
M-DEX | Seems not superior | ||
Facon et al. 2007 (IFM 99-06) | Phase III | MPT | Inferior OS |
VAD -> MEL100 | Seems not superior |
In IFM 95-01 this regimen was intended for patients aged between 65 and 75 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Some stage I patients were allowed; see text for details. In IFM 99-06 this regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years.
Chemotherapy
- 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 cycle for 12 cycles
Regimen #7
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2006 | Phase III | MPT | Seems to have inferior PFS |
This regimen was intended for patients with newly diagnosed multiple myeloma aged 60 to 85 years.
Chemotherapy
- 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 cycle for 6 cycles
Regimen #8
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.
Chemotherapy
- Melphalan (Alkeran) 0.15 mg/kg PO once per day on days 1 to 7
- Prednisone (Sterapred) 20 mg PO TID on days 1 to 7
6-week cycles
References
- Alexanian R, Haut A, Khan AU, Lane M, McKelvey EM, Migliore PJ, Stuckey WJ Jr, Wilson HE. Treatment for multiple myeloma. Combination chemotherapy with different melphalan dose regimens. JAMA. 1969 Jun 2;208(9):1680-5. link to original article PubMed
- Kyle RA. Monoclonal gammopathy and multiple myeloma in the elderly. Baillieres Clin Haematol. 1987 Jun;1(2):533-57. PubMed
- Review: 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
- 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
- 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
- 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
- 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
- Update: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. link to original article 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
- Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. link to original article 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. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
- Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. link to original article 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. Epub 2011 Jun 7. link to PMC article contains verified protocol PubMed
- Update: Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article PubMed
- Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-Term Follow-Up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
- Meta-analysis: Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R, Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du Myélome; European Myeloma Network. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011 Aug 4;118(5):1239-47. Epub 2011 Jun 13. link to original article PubMed
- Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article contains verified protocol PubMed
MPR
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MPR: Melphalan, Prednisone, Revlimid (Lenalidomide)
MPR-R: Melphalan, Prednisone, Revlimid (Lenalidomide) followed by Revlimid (Lenalidomide) maintenance
MPL: Melphalan, Prednisone, Lenalidomide
Regimen #1
Study | Evidence | Comparator | Efficacy |
Magarotto et al. 2016 (EMN01) | Phase III | CPR | Might have superior PFS |
Rd | Might have superior PFS |
This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years) or coexisting comorbidities.
Chemotherapy
- Melphalan (Alkeran) as follows:
- Age 65 to 75 years: 0.18 mg/kg PO once per day on days 1 to 4
- Age > than 75 years: 0.13 mg/kg PO once per day on days 1 to 4
- Prednisone (Sterapred) 1.5 mg/kg PO once per day on days 1 to 4
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
Supportive medications
- Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
28-day cycle for 9 cycles
Patients were then randomized to lenalidomide maintenance versus lenalidomide & prednisone maintenance.
Regimen #2, "MPR-R"
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2007 | Phase II | ||
Palumbo et al. 2012 (MM-015) | Phase III | MP | Superior PFS |
MPR | Superior PFS | ||
Zweegman et al. 2016 (HOVON87/NMSG18) | Phase III | MPT-T | Seems not superior |
In Palumbo et al. 2007 this regimen was intended for newly diagnosed multiple myeloma patients ≥ 65 years, or younger if ineligible for high-dose therapy. In MM-015 this regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (≥65 years of age). In HOVON87/NMSG18 this regimen was intended for patients >65 years of age or patients ≤65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.
Chemotherapy
- 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
Supportive medications (varies depending on reference):
- HOVON87/NMSG18:
- Aspirin 75 or 80 mg PO once per day or carbasalate calcium 100 mg PO once per day
- Patients with a history of VTE received LMWH instead
- Bisphosphonates at physician discretion
- Prophylactic antibiotics at physician discretion
- Aspirin 75 or 80 mg PO once per day or carbasalate calcium 100 mg PO once per day
- MM-015: 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
28-day cycle for 9 cycles
Followed by lenalidomide maintenance.
Regimen #3, "mPR-R"
Study | Evidence | Comparator | Efficacy |
Stewart et al. 2015 (ECOG E1A06) | Phase III | MPT-T | Seems to have non-inferior PFS |
This regimen was intended for patients who were ≥65 years or were <65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.
Chemotherapy
- Melphalan (Alkeran) 5 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
Supportive medications
- Aspirin was required (dose not specified)
- Full anticoagulation was used for patients at "higher risk" for DVT
- Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"
28-day cycle for 12 cycles
Followed by lenalidomide maintenance.
Regimen #4
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2012 (MM-015) | Phase III | MP | Seems not superior |
MPR-R | Inferior PFS |
This regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (≥65 years of age).
Chemotherapy
- 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
Supportive medications
- Aspirin 75 to 100 mg PO once per day as thromboprophylaxis
28-day cycle for 9 cycles
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-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article contains verified protocol PubMed
- Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
- Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed
- Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed
MPT
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MPT: Melphalan, Prednisone, Thalidomide
Regimen #1, "MPT-T"
Study | Evidence | Comparator | Efficacy |
Zweegman et al. 2016 (HOVON87/NMSG18) | Phase III | MPR-R | Seems not superior |
This regimen was intended for patients >65 years of age or patients ≤65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.
Chemotherapy
- 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
- Thalidomide (Thalomid) 200 mg PO once per day
Supportive medications
- Aspirin 75 or 80 mg PO once per day or carbasalate calcium 100 mg PO once per day
- Patients with a history of VTE received LMWH instead
- Bisphosphonates at physician discretion
- Prophylactic antibiotics at physician discretion
28-day cycle for 9 cycles
Treatment followed by thalidomide maintenance.
Regimen #2, "MPT-T"
Study | Evidence | Comparator | Efficacy |
Stewart et al. 2015 (ECOG E1A06) | Phase III | mPR-R | Seems to have non-inferior PFS |
This regimen was intended for patients who were ≥65 years or were <65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.
Chemotherapy
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
- Thalidomide (Thalomid) 100 mg PO once per day
Supportive medications
- Aspirin was required (dose not specified)
- Full anticoagulation was used for patients at "higher risk" for DVT
- Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"
28-day cycle for 12 cycles
Treatment followed by thalidomide maintenance.
Regimen #3
Study | Evidence | Comparator | Efficacy |
Benboubker et al. 2014 (FIRST) | Phase III | LD | Seems to have inferior OS |
LD18 | Might have inferior OS |
This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were ≥65 years of age or were <65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose.
Chemotherapy
- Melphalan (Alkeran) starting dose as follows:
- Age ≤75 AND ANC ≥1500 AND Platelets ≥100,000: 0.25 mg/kg PO once per day on days 1 to 4
- Age >75 AND ANC ≥1500 AND Platelets ≥100,000: 0.2 mg/kg PO once per day on days 1 to 4
- Age ≤75 AND ANC <1500 but ≥1000 OR Platelets <100,000 but ≥50,000: 0.125 mg/kg PO once per day on days 1 to 4
- Age >75 AND ANC <1500 but ≥1000 OR Platelets <100,000 but ≥50,000: 0.1 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) starting dose as follows:
- Age ≤75: 200 mg PO once per day
- Age >75: 100 mg PO once per day
42-day cycle for 12 cycles
Regimen #4, "MP-T"
Study | Evidence | Comparator | Efficacy |
Wijermans et al. 2010 (HOVON 49) | Phase III | MP | Might have superior OS |
This regimen was intended for patients with previously untreated MM older than age 65 years.
Chemotherapy
- 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
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."
- During induction therapy, low molecular weight heparin use recommended with Nadroparin (Fraxiparine) 2,850 units anti-Xa (for patients >90 kg, dose of 5,700 units anti-Xa)
28-day cycle for 8 cycles
Thalidomide continues at 200 mg PO once per day for 28 days, followed by maintenance thalidomide.
Regimen #5
Study | Evidence | Comparator | Efficacy |
Hulin et al. 2009 (IFM 01/01) | Phase III | MP | Seems to have superior OS |
This regimen was intended for patients who had stage II or III newly diagnosed multiple myeloma according to the Durie-Salmon criteria and were at least 75 years of age. Certain stage I patients were allowed; see text for details.
Chemotherapy
- 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 cycle for 12 cycles
Regimen #6
Study | Evidence | Comparator | Efficacy |
Facon et al. 2007 (IFM 99-06) | Phase III | MP | Superior OS |
MEL100 | Seems to have superior OS |
This regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years.
Chemotherapy
- 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 4 weeks on therapy to maximum dose of 400 mg once per day
42-day cycle for 12 cycles
Regimen #7
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2006 | Phase III | MP | Seems to have superior PFS |
This regimen was intended for patients with newly diagnosed multiple myeloma aged 60 to 85 years.
Chemotherapy
- 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 cycle for 6 cycles
Patients then proceeded to maintenance thalidomide.
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
- 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
- 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
- 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
- Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. link to original article 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. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
- Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. link to original article PubMed
- Meta-analysis: Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R, Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du Myélome; European Myeloma Network. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011 Aug 4;118(5):1239-47. Epub 2011 Jun 13. link to original article PubMed
- Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. link to original article link to supplemental appendix contains verified protocol PubMed
- Update: Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial. J Clin Oncol. 2016 Jun 20. [Epub ahead of print] link to original article PubMed
- Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
- Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed
PAD
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PAD: PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
PAd: PS-341 (Bortezomib), Adriamycin (Doxorubicin), low-dose dexamethasone
Note that this regimen is sometimes called VAD but this can create a lot of confusion with the "original" VAD which uses Vincristine.
VAD: Velcade (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
Regimen #1, "PAd"
Study | Evidence | Comparator | Efficacy |
Mai et al. 2015 (MM5) | Phase III | VCD | Non-inferior VGPR or better rate |
This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 SC 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) 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
Supportive medications
- Cotrimoxazole (dose not specified)
- Acyclovir (Zovirax) (dose not specified)
- Bisphosphonate IV every 4 weeks
28-day cycle for 3 cycles
Treatment followed by high-dose melphalan & autologous hematopoietic cell transplant.
Regimen #2
Study | Evidence | Comparator | Efficacy |
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4) | Phase III | VAD | Seems to have superior OS |
This regimen was intended for patients 18 to 65 years of age with newly diagnosed MM, Durie-Salmon stage II to III, WHO performance status 0 to 2, or WHO 3 when caused by MM. Observed efficacy is for induction PAD -> transplant -> maintenance bortezomib compared with induction VAD -> transplant -> maintenance thalidomide.
Chemotherapy
- 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
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)
28-day cycle for 3 cycles
Stem cells collected 4 to 6 weeks after induction therapy; patients proceed to receive single autologous hematopoietic cell transplant (HOVON-65) or tandem autologous hematopoietic cell transplant (GMMG-HD4).
References
- Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
- Subgroup analysis: Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. link to original article PubMed
- Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed
RD; RevDex; Rd; Len-Dex
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RD: Revlimid (Lenalidomide), Dexamethasone
RevDex: Revlimid (Lenalidomide), Dexamethasone
Rd: Revlimid (Lenalidomide), low dose dexamethasone
Len-Dex: Lenalidomide, Dexamethasone
Regimen #1, "Rd"
Study | Evidence | Comparator | Efficacy |
Magarotto et al. 2016 (EMN01) | Phase III | CPR | Seems not superior |
MPR | Might have inferior PFS |
This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (≥65 years) or coexisting comorbidities.
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) as follows:
- Age 65 to 75 years: 40 mg PO once per day on days 1, 8, 15, 22
- Age >75 years: 20 mg PO once per day on days 1, 8, 15, 22
Supportive medications
- Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
28-day cycle for 9 cycles
Patients were then randomized to lenalidomide maintenance versus lenalidomide & prednisone maintenance.
Regimen #2
Study | Evidence | Comparator | Efficacy |
Benboubker et al. 2014 (FIRST) | Phase III | Rd18 | Might have superior OS |
MPT | Seems to have superior OS |
This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were ≥65 years of age or were <65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. This was superior to LD18, below. See supplemental appendix for dose adjustments from the starting dose.
Chemotherapy
- Lenalidomide (Revlimid) starting dose as follows:
- Normal renal function: 25 mg PO once per day on days 1 to 21
- Moderate renal impairment (CrCl 30 to 50 ml/min): 10 mg PO once per day on days 1 to 21
- Severe renal impairment (CrCl <30 ml/min): 15 mg PO once every other day on days 1 to 21
- Dexamethasone (Decadron) starting dose as follows:
- Age ≤75: 40 mg PO once per day on days 1, 8, 15, 22
- Age >75: 20 mg PO once per day on days 1, 8, 15, 22
28-day cycle given until disease progression
Regimen #3, "Rd18"
Study | Evidence | Comparator | Efficacy |
Benboubker et al. 2014 (FIRST) | Phase III | Rd continuous | Might have inferior OS |
MPT | Might have superior OS |
This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were ≥65 years of age or were <65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose. This was inferior to LD, above. See supplemental appendix for dose adjustments from the starting dose.
Chemotherapy
- Lenalidomide (Revlimid) starting dose as follows:
- Normal renal function: 25 mg PO once per day on days 1 to 21
- Moderate renal impairment (CrCl 30-50 ml/min): 10 mg PO once per day on days 1 to 21
- Severe renal impairment (CrCl <30 ml/min): 15 mg PO once every other day on days 1 to 21
- Dexamethasone (Decadron) starting dose as follows:
- Age ≤75: 40 mg PO once per day on days 1, 8, 15, 22
- Age >75: 20 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 18 cycles
Regimen #4, "Rd"
Study | Evidence | Comparator | Efficacy |
Rajkumar et al. 2010 (ECOG E4A03) | Phase III | RD | Superior OS |
Gay et al. 2010 | Retrospective | ||
Gay et al. 2015 | Non-randomized portion of RCT |
In ECOG E4A03 this is the low-dose dexamethasone arm, and was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h. Gay et al. 2015 was intended for transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger.
Chemotherapy
- 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
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 mandatory (added mid-protocol after excess rates of DVT)
28-day cycle for 4 cycles (see below)
Responding patients in ECOG E4A03 could choose after 4 cycles to proceed to high-dose melphalan with autologous hematopoietic cell transplant or to continue Rd until progression of disease or intolerable toxicity; nonresponders were transitioned to Thal-Dex (details not described). Patients in Gay et al. 2015 were randomized after 4 cycles to tandem high-dose melphalan with autologous hematopoietic cell transplant versus CRD consolidation.
Regimen #5, "RD"
Study | Evidence | Comparator | Efficacy |
Rajkumar et al. 2010 (ECOG E4A03) | Phase III | Rd | Inferior OS |
This is the high-dose dexamethasone arm, and was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.
Chemotherapy
- 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
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 mandatory (added mid-protocol after excess rates of DVT)
28-day cycle for 4 cycles (see below)
Responding patients could choose after 4 cycles to proceed to high-dose melphalan with autologous hematopoietic cell transplant or to continue RD until progression of disease or intolerable toxicity; nonresponders were transitioned to Thal-Dex (details not described).
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 link to PMC article contains verified protocol PubMed
- Retrospective: Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. link to original article contains verified protocol PubMed
- Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010 Dec 23;116(26):5838-41. Epub 2010 Sep 27. link to original article PubMed
- Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article PubMed
- Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. link to original article link to supplemental appendix contains verified protocol PubMed
- Update: Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated Outcomes and Impact of Age With Lenalidomide and Low-Dose Dexamethasone or Melphalan, Prednisone, and Thalidomide in the Randomized, Phase III FIRST Trial. J Clin Oncol. 2016 Jun 20. [Epub ahead of print] link to original article PubMed
- Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
- Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed
RVD; VDR; VRD
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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Kumar et al. 2012 (EVOLUTION) | Randomized Phase II | VDC | Seems not superior |
VDC-mod | Seems not superior | ||
VDCR | Seems not superior |
This regimen was intended for patients ≥ 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status ≥ 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.
Chemotherapy
- 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 cycle for 8 cycles
Treatment followed by bortezomib consolidation.
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
RVDC; VDCR
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RVDC: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VDCR: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide, Revlimid (Lenalidomide)
Regimen
Study | Evidence | Comparator | Efficacy |
Kumar et al. 2012 (EVOLUTION) | Randomized Phase II | VDC | Seems not superior |
VDC-mod | Seems not superior | ||
VDR | Seems not superior |
This regimen was intended for patients ≥ 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status ≥ 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.
Chemotherapy
- 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
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"
21-day cycle for 8 cycles
Treatment followed by bortezomib consolidation.
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
TAD
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TAD: Thalidomide, Adriamycin (Doxorubicin), Dexamethasone
Regimen
To be completed
References
- Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article PubMed
TD
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TD: Thalidomide, Dexamethasone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Rosiñol et al. 2012 (PETHEMA GEM05MENOS65) | Phase III | VTD | Seems to have inferior PFS |
VBMCP/VBAD/B | Not reported |
This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were ≤ 65 years of age with measurable serum and/or urine M protein.
Chemotherapy
- Thalidomide (Thalomid) as follows:
- Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
- Cycle 2 onwards: 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
Supportive medications
- Low-molecular weight heparin or Aspirin recommended
28-day cycle for 6 cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
Cavo et al. 2010 (GIMEMA MM-BO2005) | Phase III | VTD | Inferior CR/nCR rate |
This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.
Induction therapy
- Thalidomide (Thalomid) as follows:
- Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21
- Cycles 2 & 3: 200 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
21-day cycle for 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 hematopoietic 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 hematopoietic cell rescue
Wait until 3 months after second transplant, then proceed to thalidomide & dexamethasone therapy
Thalidomide & dexamethasone consolidation
- 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 cycle for 2 cycles
Treatment followed by dexamethasone maintenance.
Supportive medications
- Acyclovir (Zovirax) prophylaxis recommended
Regimen #3
Study | Evidence | Comparator | Efficacy |
Rajkumar et al. 2008 | Phase III | Dexamethasone | Superior TTP |
This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.
Chemotherapy
- Thalidomide (Thalomid) as follows:
- Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
- Cycle 2 onwards: 200 mg PO once per day on days 1 to 28
- Dexamethasone (Decadron) as folows:
- Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycle 5 onwards: 40 mg PO once per day on days 1 to 4
28-day cycles
Regimen #4
Study | Evidence | Comparator | Efficacy | Toxicity |
Rajkumar et al. 2002 | Phase II | |||
Rajkumar et al. 2006 | Phase III | Dexamethasone | Seems to have superior RR | Inferior toxicity |
In Rajkumar et al. 2006 his regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (≥ 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1.0 g/dL and/or urine monoclonal protein ≥ 200 mg/24 h.
Chemotherapy
- Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 28
- Dexamethasone (Decadron) as follows:
- Odd-numbered cycles: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Even-numbered cycles: 40 mg PO once per day on days 1 to 4
28-day cycles
Regimen #5
Study | Evidence |
Cavo et al. 2004 (Bologna 2002) | Phase II |
Chemotherapy
- Thalidomide (Thalomid) as follows:
- Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to end of month
- Cycles 2 to 4: 200 mg PO once per day on days 1 to end of month
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycles 2 & 4: 40 mg PO once per day on days 1 to 4
Monthly cycle for 4 cycles
Responders proceeded to autologous hematopoietic cell transplant.
References
- 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
- 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
- Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, de Vivo A, Palareti G, Tura S, Baccarani M. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica. 2004 Jul;89(7):826-31. link to original article PubMed
- Sub-analysis: Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005 Jul 1;106(1):35-9. Epub 2005 Mar 10. link to original article contains protocol 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. Epub 2010 Dec 9. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. link to original article PubMed
- Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. 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
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VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
VAd: Vincristine, Adriamycin (Doxorubicin), low-dose dexamethasone
Note: VAD is given as a bolus or a continuous infusion regimen; see variants for details.
Regimen #1
Study | Evidence | Comparator | Efficacy |
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4) | Phase III | PAD | Seems to have inferior OS |
This regimen was intended for patients 18 to 65 years of age with newly diagnosed MM, Durie-Salmon stage II to III, WHO performance status 0 to 2, or WHO 3 when caused by MM. Observed efficacy is for induction PAD -> transplant -> maintenance bortezomib compared with induction VAD -> transplant -> maintenance thalidomide.
Chemotherapy
- 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
Supportive medications
- 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)
28-day cycle for 3 cycles
Stem cells collected 4 to 6 weeks after induction therapy; patients proceed to receive single autologous hematopoietic cell transplant (HOVON-65) or tandem autologous hematopoietic cell transplant (GMMG-HD4).
Regimen #2
Study | Evidence | Comparator | Efficacy |
Harousseau et al. 2010 (IFM 2005-01) | Phase III | VD | Might have inferior PFS |
This regimen was intended for patients age ≤ 65 years with untreated symptomatic MM with measurable paraprotein in serum (>1.0 g/dL) or urine (> 0.2 g/24 h).
Chemotherapy
- Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1.6 mg)
- Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m2)
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycle 3 onwards: 40 mg PO once per day on days 1 to 4
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."
28-day cycle for 4 cycles
Patients were then randomized to DCEP consolidation or went directly to autologous hematopoietic cell transplant.
Regimen #3, "VAd"
Study | Evidence | Comparator | Efficacy |
Rifkin et al. 2006 | Phase III | DVd | Non-inferior ORR |
This regimen was intended for patients ≥ 18 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria.
Chemotherapy
- Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 1.6 mg)
- Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 36 mg/m2)
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles
Regimen #4, VAD bolus
Study | Evidence | Comparator | Efficacy |
Dimopoulos et al. 2003 | Phase III | VAD Doxil | Seems not superior |
This regimen was intended for all patients with previously untreated multiple myeloma who were considered candidates for systemic treatment.
Chemotherapy
- 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) as follows:
- Cycles 1 & 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycles 2 & 4: 40 mg PO once per day on days 1 to 4
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"
4-week cycle for 4 cycles
References
- 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
- Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. link to original article PubMed
- Update: Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM Group. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article 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
- Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
- 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
- Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
VAD-P
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VAD-P: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Prednisone
Regimen
Study | Evidence | Comparator | Efficacy |
Berenson et al. 2002 (SWOG 9210) | Phase III | VAD-P/Q | Seems not superior |
Chemotherapy
- Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1.6 mg)
- Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m2)
- Poor-risk patients received 6.75 mg/m2/day in cycle 1 (total dose 27 mg/m2), 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 for 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 randomized to low-dose prednisone maintenance versus high-dose prednisone maintenance.
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
VAD-P/Q
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VAD-P/Q: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Prednisone, Quinine
Regimen
Study | Evidence | Comparator | Efficacy |
Berenson et al. 2002 (SWOG 9210) | Phase III | VAD-P | Seems not superior |
Chemotherapy
- Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 2 to 5 (total dose per cycle: 1.6 mg)
- Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 4 days on days 2 to 5 (total dose per cycle: 36 mg/m2)
- Poor-risk patients received 6.75 mg/m2/day in cycle 1 (total dose 27 mg/m2), 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 cycle for 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 randomized to low-dose prednisone maintenance versus high-dose prednisone maintenance.
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
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VD: Velcade (Bortezomib), Dexamethasone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Niesvizky et al. 2015 (UPFRONT) | Phase III | VMP | Seems not superior |
VTD | Seems not superior |
This regimen was meant for transplant ineligible patients.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
- Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5
21-day cycle for 8 cycles
Treatment followed by bortezomib maintenance.
Regimen #2
Study | Evidence | Comparator | Efficacy |
Moreau et al. 2011 (IFM 2007-02) | Phase III | vtD | Inferior VGPR rate |
This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (> 1 g/dL) or urine (> 0.2 g/24 hours).
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
- Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4
21-day cycle for 4 cycles
All patients then underwent high dose melphalan -> autologous hematopoietic cell transplant.
Regimen #3
Study | Evidence | Comparator | Efficacy |
Harousseau et al. 2010 (IFM 2005-01) | Phase III | VAD | Might have superior PFS |
This regimen was intended for patients age ≤ 65 years with untreated symptomatic MM with measurable paraprotein in serum (>1.0 g/dL) or urine (> 0.2 g/24 h).
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12
- Cycles 3 & 4: 40 mg PO once per day on days 1 to 4
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."
21-day cycle for 4 cycles
Patients were then randomized to DCEP consolidation or went directly to autologous hematopoietic cell transplant.
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
- Subgroup analysis: 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
- Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article contains verified protocol PubMed
- Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed
VDC; VDC-mod
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VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VCD: Velcade (Bortezomib), Cyclophosphamide, Dexamethasone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Moreau et al. 2016 (IFM 2013-04) | Phase III | VTD | Seems to have inferior ORR rate |
This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (> 1 g/dL) or urine (> 0.2 g/24 hours).
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
- Cyclophosphamide (Cytoxan) 500 mg/m2 PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
21-day cycle for 4 cycles
All patients then underwent autologous hematopoietic cell transplant, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center.
Regimen #2, "VCD"
Study | Evidence | Comparator | Efficacy |
Mai et al. 2015 (MM5) | Phase III | PAd | Non-inferior VGPR or better rate |
This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
- Cyclophosphamide (Cytoxan) 900 mg/m2 IV once on day 1
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
Supportive medications
- Cotrimoxazole (dose not specified)
- Acyclovir (Zovirax) (dose not specified)
- Bisphosphonate IV every 4 weeks
21-day cycle for 3 cycles
Treatment followed by high-dose melphalan & autologous hematopoietic cell transplant.
Regimen #3, "VDC"
Study | Evidence | Comparator | Efficacy |
Kumar et al. 2012 (EVOLUTION) | Randomized Phase II | VDR | Seems not superior |
VDCR | Seems not superior |
This regimen was intended for patients ≥ 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status ≥ 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. The only difference between this regimen and VDC-mod is the number of cyclophosphamide doses.
Chemotherapy
- 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
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"
21-day cycle for 8 cycles
Treatment followed by bortezomib consolidation.
Regimen #4, "VDC-mod"
Study | Evidence | Comparator | Efficacy |
Kumar et al. 2012 (EVOLUTION) | Randomized Phase II, <20 in this arm | VDR | Seems not superior |
VDCR | Seems not superior |
This regimen was intended for patients ≥ 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status ≥ 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. This arm only had 17 patients enrolled; other arms of the EVOLUTION trial all had > 20 patients enrolled. The only difference between this and regimen #1 is the number of cyclophosphamide doses.
Chemotherapy
- 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, 15
Supportive medications
- Aspirin 325 mg PO once per day
- Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used instead, based on physician discretion
- PCP prophylaxis recommended
- Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
- Bisphosphonates could be used "as necessary"
21-day cycle for 8 cycles
Treatment followed by bortezomib consolidation.
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
- Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article PubMed
- Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed
- Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. link to original article contains verified protocol PubMed
VMP
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VMP: Velcade (Bortezomib), Melphalan, Prednisone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Niesvizky et al. 2015 (UPFRONT) | Phase III | VD | Seems not superior |
VTD | Seems not superior |
This regimen was meant for transplant ineligible patients.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4 every other cycle
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4 every other cycle
21-day cycle for 8 cycles
Treatment followed by bortezomib maintenance.
Regimen #2
Study | Evidence | Comparator | Efficacy |
San Miguel et al. 2008 (VISTA) | Phase III | MP | Superior OS |
Palumbo et al. 2010 | Phase III | VMPT-VT | Seems to have inferior OS |
San-Miguel et al. 2014 | Randomized Phase II | VMP & Siltuximab | Seems not superior |
In Palumbo et al. 2010 and VISTA this regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (≥65 years) or coexisting conditions.
Chemotherapy
- Bortezomib (Velcade) as follows:
- Cycles 1 to 4: 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32
- Cycles 5 to 9: 1.3 mg/m2 IV bolus once per day on days 1, 8, 22, 29
- 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
Supportive medications
- Bisphosphonates given to patients with myeloma-associated bone disease unless contraindicated (only mentioned in San Miguel et al. 2008)
42-day cycle for 9 cycles
Regimen #3
Study | Evidence | Comparator | Efficacy |
Mateos et al. 2010 (GEM2005) | Phase III | VTP | Seems to have superior OS |
This regimen was intended for patients with untreated multiple myeloma, 65 years and older.
First Cycle
- 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
Supportive medications
- Patients with bone disease received bisphosphonates
- Prophylactic aciclovir was recommended.
42-day cycle for 1 cycle, then
Remainder of induction
- 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
Supportive medications
- Patients with bone disease received bisphosphonates
- Prophylactic aciclovir was recommended.
35-day cycle for 5 cycles
Treatment followed by bortezomib & prednisone maintenance versus VT maintenance.
Regimen #4, weekly bortezomib
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2010 | Phase III | VMPT-VT | Seems to have inferior OS |
This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (≥65 years) or coexisting conditions. This dosing is the result of a mid-protocol amendment.
Chemotherapy
- 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 cycle for 9 cycles
References
- Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006 Oct 1;108(7):2165-72. Epub 2006 Jun 13. link to original article PubMed
- Update: Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Garcia-Sanchez P, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, Alegre A, de Arriba F, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica. 2008 Apr;93(4):560-5. Epub 2008 Mar 5. link to original article 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 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
- Update: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. link to original article 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
- Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
- Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. 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. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
- Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article contains verified protocol PubMed
- Subset analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article PubMed
- Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article contains verified protocol PubMed
- San-Miguel J, Bladé J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, Robak T, Prasad SV, Tee Goh Y, Laubach J, Spencer A, Mateos MV, Palumbo A, Puchalski T, Reddy M, Uhlar C, Qin X, van de Velde H, Xie H, Orlowski RZ. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood. 2014 Jun 26;123(26):4136-42. Epub 2014 May 15. Erratum in: Blood. 2014 Aug 14;124(7):1201. link to original article refers to protocol in San Miguel et al. 2008 PubMed
- Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed
VMP -> Rd
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VMP: Velcade (Bortezomib), Melphalan, Prednisone
Rd: Revlimid (Lenalidomide), low dose dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Mateos et al. 2015 (PETHEMA GEM05) | Phase III | VMP/Rd | Seems not superior |
This regimen was intended for patients aged ≥65 years with newly diagnosed, untreated, symptomatic, measurable MM.
Chemotherapy, VMP portion, first cycle
- 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 for 1 cycle, then:
Chemotherapy, VMP portion, remainder
- Bortezomib (Velcade) 1.3 mg/m2 IV once per week 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
28-day cycle for 8 cycles, followed by:
Chemotherapy, Rd portion
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
28-day cycle for 9 cycles
Supportive medications
- During bortezomib therapy:
- During lenalidomide therapy:
- Mandatory thromboprophylaxis with either Aspirin or low–molecular weight heparin
References
- Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. link to original article contains verified protocol PubMed
VMP/Rd
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VMP: Velcade (Bortezomib), Melphalan, Prednisone
Rd: Revlimid (Lenalidomide), low dose dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Mateos et al. 2015 (PETHEMA GEM05) | Phase III | VMP -> Rd | Seems not superior |
This regimen was intended for patients aged ≥65 years with newly diagnosed, untreated, symptomatic, measurable MM.
Chemotherapy, VMP portion, first cycle
- 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 for 1 cycle, then Rd cycle #1:
Chemotherapy, VMP portion, remaining cycles
- Bortezomib (Velcade) 1.3 mg/m2 IV once per week 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
28-day cycle for 8 cycles, alternating with Rd:
Chemotherapy, Rd portion
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
28-day cycle alternating with VMP x 9 cycles
Supportive medications
- During bortezomib therapy:
- During lenalidomide therapy:
- Mandatory thromboprophylaxis with either Aspirin or low–molecular weight heparin
References
- Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. link to original article contains verified protocol PubMed
VMPT
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VMPT: Velcade (Bortezomib), Melphalan, Prednisone, Thalidomide
Regimen #1
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2010 | Phase III | VMP | Seems to have superior OS |
This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (≥ 65 years) or coexisting comorbidities.
Chemotherapy
- Bortezomib (Velcade) as follows:
- Cycles 1 to 4: 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32
- Cycles 5 to 9: 1.3 mg/m2 IV bolus once per day on days 1, 8, 22, 29
- 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 cycle for 9 cycles
Treatment followed by VT maintenance therapy.
Regimen #2
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2010 | Phase III | VMP | Seems to have superior OS |
This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (≥ 65 years) or coexisting comorbidities. This variant represents a mid-protocol change (in 2007) where cycle length was decreased from 6 to 5 weeks and bortezomib was changed to weekly dosing.
Chemotherapy
- 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 cycle for 9 cycles
Treatment followed by VT maintenance therapy.
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. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
- Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article contains verified protocol PubMed
- Subset analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article PubMed
- Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article contains verified protocol PubMed
VTD
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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone
vTD: low-dose velcade (Bortezomib), Thalidomide, Dexamethasone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Moreau et al. 2016 (IFM 2013-04) | Phase III | VCD | Seems to have superior ORR rate |
This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (> 1 g/dL) or urine (> 0.2 g/24 hours).
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
21-day cycle for 4 cycles
All patients then underwent autologous hematopoietic cell transplant, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center.
Regimen #2
Study | Evidence | Comparator | Efficacy |
Niesvizky et al. 2015 (UPFRONT) | Phase III | VD | Seems not superior |
VMP | Seems not superior |
This regimen was intended for patients with newly diagnosed, symptomatic, measurable MM requiring systemic therapy, and who were ineligible for stem-cell transplantation because of age (≥ 65 years), comorbidities, or personal preference.
Chemotherapy
- 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 21
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
- Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5
21-day cycle for 8 cycles
Treatment followed by bortezomib maintenance.
Regimen #3
Study | Evidence | Comparator | Efficacy |
Cavo et al. 2010 (GIMEMA MM-BO2005) | Phase III | TD | Superior CR/nCR rate |
This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.
Induction therapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) as follows:
- Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21
- Cycles 2 & 3: 200 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycle for 3 cycles, then proceed to first stem cell transplant
First stem cell transplant
- Melphalan (Alkeran) 200 mg/m2 once on day -2
- autologous hematopoietic 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 cycle 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 hematopoietic 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 cycle for 2 cycles
Patients then proceed to dexamethasone maintenance therapy.
Supportive medications
- Acyclovir (Zovirax) prophylaxis recommended
Regimen #4, "vTD"
Study | Evidence | Comparator | Efficacy |
Moreau et al. 2011 (IFM 2007-02) | Phase III | VD | Superior VGPR rate |
Lok et al. 2014 | Non-randomized |
IFM 2007-02 was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (> 1 g/dL) or urine (> 0.2 g/24 hours). Lok et al. 2014 uses the same dosing except that bortezomib is given SC.
Chemotherapy
- Bortezomib (Velcade) 1 mg/m2 IV/SC once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
- Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4
21-day cycle for 4 cycles
All patients then underwent high dose melphalan autologous hematopoietic cell transplant.
Regimen #5
Study | Evidence | Comparator | Efficacy |
Ludwig et al. 2013 | Randomized Phase II | VTDC | Seems not superior |
This regimen was intended for patients aged 18 to 70 years with previously untreated, measurable MM requiring systemic therapy, who were candidates for high-dose chemotherapy and autologous hematopoietic cell transplant.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
21-day cycle for 4 cycles
Patients who remained eligible for transplant underwent high dose melphalan autologous hematopoietic cell transplant. Transplant ineligible patients or patients achieving CR could undergo 4 additional cycles of VTD.
Regimen #6
Study | Evidence | Comparator | Efficacy |
Rosiñol et al. 2012 (PETHEMA GEM05MENOS65) | Phase III | TD | Seems to have superior PFS |
VBMCP/VBAD/B | Seems to have superior PFS |
This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were 65 years of age or younger with measurable serum and/or urine M protein.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) as follows:
- Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
- Cycles 2 to 6: 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
Supportive medications
- Low molecular weight heparin (LMWH) or Aspirin recommended
28-day cycle for 6 cycles
References
- 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
- Update: # Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article contains verified protocol PubMed
- Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. 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
- Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Ricci D, Cakana A, Enny C, Feng H, van de Velde H, Harousseau JL. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013 Jan 10;31(2):247-55. Epub 2012 Oct 22. link to original article contains verified protocol PubMed
- Update: Ludwig H, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Chaturvedi S, Ataman O, Enny C, Feng H, van de Velde H, Viterbo L. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol. 2015 Nov;171(3):344-54. Epub 2015 Jul 7. link to original article PubMed
- Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. link to original article contains verified protocol PubMed
- Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article PubMed
- Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed
- Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. link to original article contains verified protocol PubMed
VTP
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VTP: Velcade (Bortezomib), Thalidomide, Prednisone
Regimen
Study | Evidence | Comparator | Efficacy |
Mateos et al. 2010 (GEM2005) | Phase III | VMP | Seems to have inferior OS |
This regimen was intended for patients with untreated multiple myeloma, 65 years and older.
First cycle
- 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 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
Supportive medications
- Patients with bone disease received bisphosphonates
- Prophylactic aciclovir was recommended.
- Thromboprophylaxis with either Aspirin or low-molecular-weight heparin
42-day cycle for 1 cycle, then
Remainder of induction
- 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
Supportive medications
- Patients with bone disease received bisphosphonates
- Prophylactic aciclovir was recommended.
- Thromboprophylaxis with either Aspirin or low-molecular-weight heparin
35-day cycle for 5 cycles
Treatment followed by bortezomib & prednisone maintenance versus VT maintenance.
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
- Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
- Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article contains verified protocol PubMed
Untreated (including transplant ineligible), non-randomized or retrospective data
Note: most but not all multiple myeloma first-line regimens specify whether patients are transplant eligible, or not. We will begin to break this section in those respective subsections.
BDD
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BDD: Bortezomib, Doxorubicin, Dexamethasone
Regimen
Study | Evidence |
Ludwig et al. 2010 | 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)
Chemotherapy
- 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 cycle for 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. Epub 2010 Sep 7. link to original article contains verified protocol PubMed
BiRD
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BiRD: Biaxin, Revlimid (Lenalidomide), Dexamethasone
Regimen
Study | Evidence |
Niesvizky et al. 2007 | Phase II |
Chemotherapy
- Clarithromycin (Biaxin) as follows:
- Cycle 1: 500 mg PO BID on days 2 to 28
- Cycle 2 onwards: 500 mg PO BID on days 1 to 28
- Lenalidomide (Revlimid) as follows:
- Cycle 1: 25 mg PO once per day on days 3 to 21
- Cycle 2 onwards: 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) as follows:
- Cycle 1: 40 mg PO once per day on days 1, 2, 3, 8, 15, 22
- Cycle 2 onwards: 40 mg PO once per day on days 1, 8, 15, 22
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
28-day cycles
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
- Update: Rossi A, Mark T, Jayabalan D, Christos P, Zafar F, Pekle K, Pearse R, Chen-Kiang S, Coleman M, Niesvizky R. BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood. 2013 Mar 14;121(11):1982-1985. Epub 2013 Jan 8. 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
CAD
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CAD: Cyclophosphamide, Adriamycin (Doxorubicin), Dexamethasone
Regimen
This is reported as a stem cell mobilization regimen but presumably has anti-myeloma activity.
To be completed
References
- Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article PubMed
CCyd
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CCyd: Carfilzomib, Cyclophosphamide, dexamethasone
Regimen
Study | Evidence |
Bringhen et al. 2014 | Phase II |
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once per day on days 1 & 2 then 36 mg/m2 IV once per day on days 8, 9, 15, 16
- Cycles 2 to 9: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
- 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 cycle for 9 cycles
Followed by maintenance carfilzomib.
References
- Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. link to original article contains verified protocol PubMed
CMP
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CMP: Carfilzomib, Melphalan, Prednisone
Regimen
Study | Evidence |
Moreau et al. 2015 | Phase I/II |
This trial was open to patients older than 65 years of age. Although not explicitly stated, this is considered to be a transplant ineligible population in France. The carfilzomib dose of 36 mg/m2 was considered to be the MTD in this trial.
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 36 mg/m2 IV once per day on days 8, 9, 22, 23, 29, 30
- Cycles 2 to 9: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 22, 23, 29, 30
- Melphalan (Alkeran) 9 mg/m2/day PO on days 1 to 4
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 4
42-day cycle for 9 cycles
References
- Moreau P, Kolb B, Attal M, Caillot D, Benboubker L, Tiab M, Touzeau C, Leleu X, Roussel M, Chaleteix C, Planche L, Chiffoleau A, Fortin J, Avet-Loiseau H, Mary JY, Hulin C, Facon T. Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood. 2015 May 14;125(20):3100-4. Epub 2015 Mar 17. link to original article contains verified protocol PubMed
CRd
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CRd: Carfilzomib, Revlimid (Lenalidomide), (low-dose) dexamethasone
Regimen #1
Study | Evidence |
Korde et al. 2016 | Phase II |
The minimal difference between this and variant #2 below is the steroid dosing.
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once per day on days 1, 2, then 36 mg/m2 IV once per day on days 8, 9, 15, 16
- Cycles 2 to 8: 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) as follows:
- Cycle 1: 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
- Cycles 2 to 4: 20 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
- Cycles 5 to 8: 10 mg PO/IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
28-day cycle for 8 cycles
Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant. If transplant was not undertaken, patients proceeded to lenalidomide extension after the 8th cycle.
Regimen #2
Study | Evidence |
Jakubowiak et al. 2012 | Phase I/II |
This is the MTD dosing in this phase I/II trial.
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once per day on days 1, 2, then 36 mg/m2 IV once per day on days 8, 9, 15, 16
- Cycles 2 to 8: 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) as follows:
- Cycles 1 to 4: 40 mg (route not specified) once per week on days 1, 8, 15, 22
- Cycles 1 & 2 at clinician's discretion: 4 mg IV/PO once per day on days 2, 9, 16 (in addition to above)
- Cycles 5 to 8: 20 mg (route not specified) once per week on days 1, 8, 15, 22
28-day cycle for 8 cycles
Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant. If transplant was not undertaken, patients proceeded to CRd maintenance after the 8th cycle.
References
- Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
- Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. link to original article contains verified protocol PubMed
CyBorD
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CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone
Regimen #1, once per week bortezomib
Study | Evidence |
Reeder et al. 2010 | Phase II |
This regimen was described in a letter to the editor of Blood.
Chemotherapy
- 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) as follows:
- Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycles 3 & 4: 40 mg PO once per week
28-day cycle for 4 cycles
Regimen #2
Study | Evidence |
Reeder et al. 2009 | Phase II |
Chemotherapy
- 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
Supportive medications
- Proton pump inhibitor (PPI)
- Acyclovir (Zovirax)
- Quinolone antibiotic
- Antifungal mouthwash recommended
28-day cycle for 4 to 12 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 link to PMC article contains verified 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. link to original letter contains verified protocol PubMed
CYKLONE
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CYKLONE: Cyclophosphamide, Kyprolis (Carfilzomib), ThaLlidomide, DexamethasONE
Regimen
Study | Evidence |
Mikhael et al. 2015 | Phase II |
The carfilzomib dose here is the MTD dose, tested in N=29 patients.
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO on days 1, 8, 15
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
- Cycle 2 onwards: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28
- Dexamethasone (Decadron) 40 mg PO on days 1, 8, 15, 22
Supportive medications
- Aspirin or LMWH for patients intolerant of aspirin
- Acyclovir (Zovirax) 400 mg PO BID
- Antibacterials (not further specified)
- 250 to 500 ml of IVF prior to cycle 1 doses of Carfilzomib (Kyprolis) and then only for patients "at risk for tumor lysis syndrome" in subsequent cycles
28-day cycle for 4 to 12 cycles
The authors state that patients could proceed to autologous hematopoietic cell transplant after four cycles but do not provide criteria to undergo transplant as opposed to continuing CYKLONE.
References
- Mikhael JR, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, Mayo A, Nagi Reddy SK, Gano K, Dueck AC, Stewart AK. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015 Apr;169(2):219-27. Epub 2015 Feb 13. link to original article contains verified protocol PubMed
DVd
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DVd: Doxil (Liposomal Doxorubicin), Vincristine, reduced-dose dexamethasone
Regimen
Study | Evidence |
Hussein et al. 2002 | Phase II |
Chemotherapy
- 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
Supportive medications
- Vitamin B6 200 mg PO once per day to help reduce risk of palmar-plantar erythrodysesthesia (PPE)
4-week cycle for 6 to 8 cycles
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
Ixazomib, Lenalidomide, Dexamethasone
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Regimen
Study | Evidence |
Kumar et al 2014 | Phase I/II |
This is the MTD dose of this phase I/II trial.
Chemotherapy
- Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
28-day cycle for up to 12 cycles
Transplant-eligible patients could proceed to autologous hematopoietic cell transplant after 6 cycles. Patients who did not undergo transplant proceeded to ixazomib maintenance after the 12th cycle.
References
- Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A11, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. link to original article PubMed
KTd
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KTd: Kyprolis (Carfilzomib), Thalidomide, dexamethasone
Regimen
Study | Evidence |
Sonneveld et al. 2014 | Phase II |
Three cohorts are reported; optimal dose of carfilzomib is not described.
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, and:
- Cohort 1: 27 mg/m2 IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
- Cohort 2: 36 mg/m2 IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
- Cohort 3: 45 mg/m2 IV once per day on days 8, 9, 15, 16 of cycle 1 and days 1, 2, 8, 9, 15, 16 of subsequent cycles
- Thalidomide (Thalomid) 200 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
28-day cycle for 4 cycles
Treatment followed by high-dose melphalan with stem cell rescue.
References
- Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. link to original article contains verified protocol PubMed
PAD
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PAD: PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
Regimen
Study | Evidence |
Oakervee et al. 2005 | Phase II |
Chemotherapy
- 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) as follows:
- Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
- Cycles 2 to 4: 40 mg PO once per day on days 1 to 4
21-day cycle for 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
RD; RevDex; Rd; Len-Dex
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RD: Revlimid (Lenalidomide), Dexamethasone
RevDex: Revlimid (Lenalidomide), Dexamethasone
Rd: Revlimid (Lenalidomide), low dose dexamethasone
Len-Dex: Lenalidomide, Dexamethasone
Regimen
Study | Evidence |
Rajkumar et al. 2005 | Phase II |
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycle 5 onwards: 40 mg PO once per day on days 1 to 4
Supportive medications
- Aspirin 80 mg or 325 mg (depending on physician choice) PO once per day for thromboprophylaxis
28-day cycles, given until progression of disease or unacceptable toxicity
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
RP
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RP-MPR-RP: Revlimid (Lenalidomide), Prednisone, followed by Melphalan, Prednisone, Revlimid (Lenalidomide), followed by Revlimid (Lenalidomide), Prednisone
Regimen, "RP-MPR-RP"
Study | Evidence |
Falco et al. 2012 | Phase II |
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Prednisone (Sterapred) 50 mg PO three times per week
Supportive medications
- Aspirin 100 ?mg PO once per day as thromboprophylaxis during Lenalidomide (Revlimid) treatment. Unclear from protocol if this also means off weeks.
- Antiviral prophylaxis if history of VZV.
28-day cycle for 4 cycles
Treatment is followed by MPR consolidation.
References
- Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. link to original article contains verified protocol PubMed
RVD; VDR; VRD
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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
Regimen #1
Study | Evidence |
Roussel et al. 2014 | Phase II |
Chemotherapy
- 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
Supportive medications
- Low–molecular weight heparin (LMWH)
- Antiviral therapy with example valacyclovir given, for herpes zoster prevention
- Antibiotic prophylaxis with example amoxicillin given, for bacterial infections
21-day cycle for 3 cycles
Treatment followed by high-dose melphalan and autologous hematopoietic cell transplant.
Regimen #2
Study | Evidence |
Richardson et al. 2010 | Phase II |
Chemotherapy
- 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
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
21-day cycle for 4 to 8 cycles
Patients who responded and tolerated therapy could proceed to maintenance RVD.
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
- Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
Total Therapy
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Regimen
Study | Evidence |
Barlogie et al. 2007 (Total Therapy 3) | Prospective |
Total Therapy is a very complicated regimen, you are highly recommended to refer to the original protocols for further details. Total Therapy 3 is replicated here; the references for Total Therapy 2 are provided below but there are no plans to add this regimen here, for now.
Induction therapy, VTD-PACE
VTD-PACE: Velcade (Bortezomib), Thalidomide, Dexamethasone, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide
- 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 IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m2)
- Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m2)
- Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 1600 mg/m2)
- Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 160 mg/m2)
- 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 hematopoietic 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, VTD-PACE
VTD-PACE: Velcade (Bortezomib), Thalidomide, Dexamethasone, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide
Cycle 1 of consolidation starts 1.5 to 4 months after the last transplant. Cycle 2 of consolidation starts 2 to 4 months after cycle 1 of consolidation.
- 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 IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 30 mg/m2)
- Doxorubicin (Adriamycin) 7.5 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 30 mg/m2)
- Cyclophosphamide (Cytoxan) 300 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1200 mg/m2)
- Etoposide (Vepesid) 30 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 120 mg/m2)
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
VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone
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 cycle for 1 year, then proceed to maintenance therapy years 2 to 3
Maintenance therapy, years 2 & 3 - TD
TD: Thalidomide, Dexamethasone
- Thalidomide (Thalomid) 100 mg PO once every other day
- Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
28-day cycle for 2 years
References
- Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
- 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
- Update: Zangari M, van Rhee F, Anaissie E, Pineda-Roman M, Haessler J, Crowley J, Barlogie B. Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of total therapy 1. Br J Haematol. 2008 May;141(4):433-44. Epub 2008 Mar 26. link to original article link to PMC article PubMed
- Subgroup analysis: Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K, Alsayed Y, Waheed S, Petty N, Epstein J, Shaughnessy JD Jr, Tricot G, Zangari M, Zeldis J, Barer S, Crowley J. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008 Oct 15;112(8):3115-21. Epub 2008 May 20. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article 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
- Update: Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, Crowley J, Shaughnessy JD Jr, Barlogie B. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol. 2008 Mar;140(6):625-34. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
- Nair B, van Rhee F, Shaughnessy JD Jr, Anaissie E, Szymonifka J, Hoering A, Alsayed Y, Waheed S, Crowley J, Barlogie B. Superior results of Total Therapy 3 (2003-33) in gene expression profiling-defined low-risk multiple myeloma confirmed in subsequent trial 2006-66 with VRD maintenance. Blood. 2010 May 27;115(21):4168-73. Epub 2010 Feb 2. link to original article PubMed
VAD
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VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
Regimen #1
Study | Evidence |
Barlogie et al. 1984 | Phase II |
Barlogie et al. 2006 (SWOG S9321) | Non-randomized portion of RCT |
Chemotherapy
- Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 1.6 mg)
- Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 36 mg/m2)
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
Supportive medications
- Cimetidine (Tagamet) prophylaxis (dose not specified)
- Trimethoprim/Sulfamethoxazole prophylaxis (dose not specified)
5-week cycles
In Barlogie et al. 1984, treatment was given "until a maximum reduction in myeloma protein had occurred" and patients received four additional cycles of therapy beyond their best response. In SWOG S9321, patients with at least stable disease were randomized after 4 cycles to VBMCP versus melphalan & TBI -> autoHCT.
Regimen #2
Study | Evidence |
Segeren et al. 1999 | Phase II |
Chemotherapy
- 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
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"
4-week cycles
Regimen #3
Study | Evidence |
Cavo et al. 2007 (Bologna 96) | Non-randomized portion of RCT |
This regimen was intended for patients with a confirmed diagnosis of symptomatic or progressive MM, an upper age limit of 60 years, and previously untreated.
Chemotherapy
- Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1.6 mg)
- Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 36 mg/m2)
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 3: 40 mg PO once per day on days 1 to 4
- Cycles 2 & 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
28-day cycle for 4 cycles
Responders were randomized to single autologous hematopoietic cell transplant versus tandem autologous hematopoietic cell 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
- Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. link to original article contains verified protocol PubMed
- Sub-group analysis: Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005 Jul 1;106(1):35-9. Epub 2005 Mar 10. link to original article contains protocol PubMed
- Barlogie B, Kyle RA, Anderson KC, Greipp PR, Lazarus HM, Hurd DD, McCoy J, Moore DF Jr, Dakhil SR, Lanier KS, Chapman RA, Cromer JN, Salmon SE, Durie B, Crowley JC. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol. 2006 Feb 20;24(6):929-36. Epub 2006 Jan 23. Erratum in: J Clin Oncol. 2006 Jun 10;24(17):2687. Moore, Dennis F Jr [added]. link to original article refers to protocol in Barlogie et al. 1984 PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
VAD-DCEP
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VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol (Cisplatin)
Regimen
Study | Evidence |
Corso et al. 2004 | Phase II |
Chemotherapy, VAD portion
- Vincristine (Oncovin) 2 mg IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Dexamethasone (Decadron) 40 mg IV once per day on days 1 to 4, 14 to 17
Two cycles; time intervals were not specified.
Chemotherapy, DCEP portion
Stem cells were mobilized and collected after each course of therapy.
- Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
- Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m2)
- Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m2)
- Cisplatin (Platinol) 10 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 40 mg/m2)
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 48 hours after chemotherapy and continuing through stem cell collection
Two courses; time intervals were not specified.
Treatment followed by high dose melphalan with autologous hematopoietic cell transplant.
References
- Corso A, Barbarano L, Zappasodi P, Cairoli R, Alessandrino EP, Mangiacavalli S, Ferrari D, Fava S, Fiumanò M, Frigerio G, Isa L, Luraschi A, Klersy C, De Paoli A, Vergani C, Banfi L, Perego D, Ucci G, Pinotti G, Savarè M, Uziel L, Vismara A, Morra E, Lazzarino M. The VAD-DCEP sequence is an effective pre-transplant therapy in untreated multiple myeloma. Haematologica. 2004 Sep;89(9):1124-7. link to original article contains verified protocol PubMed
VD
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VD: Velcade (Bortezomib), Dexamethasone
Regimen
Study | Evidence |
Girnius et al. 2014 | Phase II |
Chemotherapy
- Bortezomib (Velcade) 1.6 mg/m2 IV once per week on days 1, 8, 15, 22
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
35-day cycle for up to 6 cycles based on response and tolerance of side effects
References
- Girnius SK, Lee S, Kambhampati S, Rose MG, Mohiuddin A, Houranieh A, Zimelman A, Grady T, Mehta P, Behler C, Hayes TG, Efebera YA, Prabhala RH, Han A, Yellapragada SV, Klein CE, Roodman GD, Lichtenstein A, Munshi NC. A Phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation. Br J Haematol. 2015 Apr;169(1):36-43. Epub 2015 Jan 8. Epub 2014 Sep 18. link to original article contains verified protocol PubMed
VDD; PAD; DVD
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VDD: Velcade (Bortezomib), Doxil (Liposomal doxorubicin), Dexamethasone
PAD: PS-341 (Bortezomib), liposomal Adriamycin (Doxorubicin), Dexamethasone
DVD: Doxil (Liposomal doxorubicin), Velcade (Bortezomib), Dexamethasone
Regimen #1
Study | Evidence |
Berenson et al. 2011 | Phase II |
Chemotherapy
- Doxorubicin liposomal (Doxil) 5 mg/m2 IV once per day on days 1, 4, 8, 11
- Bortezomib (Velcade) 1.0 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 40 mg IV once per day on days 1, 4, 8, 11
28-day cycle for up to 8 cycles
Regimen #2
Study | Evidence |
Palumbo et al. 2010 | Phase II |
Chemotherapy
- 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) as follows:
- Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
- Cycles 2 to 4: 40 mg PO once per day on days 1 to 4
Supportive medications
- Acyclovir (Zovirax) recommended during Bortezomib (Velcade) therapy
21-day cycle for 4 cycles
Treatment followed by high dose melphalan with autologous hematopoietic cell transplant.
Regimen #3
Study | Evidence |
Jakubowiak et al. 2009 | Phase II |
Chemotherapy
- 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) as follows:
- Cycle 1: 40 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, 4, 5, 8, 9, 11, 12
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
21-day cycle for 6 cycles
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
- Update: Dytfeld D, Griffith KA, Friedman J, Lebovic D, Harvey C, Kaminski MS, Jakubowiak AJ. Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. Leuk Lymphoma. 2011 Jul;52(7):1271-80. 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
- 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
- Berenson JR, Yellin O, Chen CS, Patel R, Bessudo A, Boccia RV, Yang HH, Vescio R, Yung E, Mapes R, Eades B, Hilger JD, Wirtschafter E, Hilger J, Nassir Y, Swift RA. A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol. 2011 Dec;155(5):580-7. Epub 2011 Sep 26. link to original article contains verified protocol PubMed
VMP
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VMP: Velcade (Bortezomib), Melphalan, Prednisone
Regimen, short-course bortezomib
Study | Evidence |
Gasparetto et al. 2010 | Phase II |
Chemotherapy
- 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
Supportive medications
- Bisphosphonates recommended
- Acyclovir (Zovirax) (dose not specified) recommended
28-day cycle for up to 6 cycles; treatment could be given beyond 6 cycles at investigator discretion
References
- 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
VTD
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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone
Regimen
Study | Evidence |
Kaufman et al. 2010 | Retrospective |
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day 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 cycle for 3 to 4 cycles
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
VTD-PACE
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VTD-PACE: Velcade (Bortezomib), Thalidomide, Dexamethasone, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide
Regimen
Study | Evidence |
Barlogie et al. 2007 (Total Therapy 3) | Prospective |
Note: this is the induction therapy used in Total Therapy 3. We are not aware of other sources prospectively describing VTD-PACE.
Chemotherapy
- 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 IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m2)
- Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 40 mg/m2)
- Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 1600 mg/m2)
- Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 4 days on days 4 to 7 (total dose per cycle: 160 mg/m2)
Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart
References
- 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
- Retrospective: Abstract: Preet Paul Singh, Wilson I. Gonsalves, Vinay Gupta, Francis Buadi, Martha Lacy, Angela Dispenzieri, Morie Gertz, Suzanne R. Hayman, David Dingli, Stephen J. Russell, John Anthony Lust, Steven R. Zeldenrust, Prashant Kapoor, Arleigh Robertson McCurdy, S. Vincent Rajkumar, Shaji Kumar. Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma. J Clin Oncol 31, 2013 (suppl; abstr 8600) link to abstract
Consolidation after upfront therapy
Note that there is no crisp distinction between consolidation and maintenance. Generally regimens that are intended for a long or indefinite duration would be considered maintenance, whereas regimens with a short intended course would be considered consolidation.
DCEP
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DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol (Cisplatin)
Regimen
Study | Evidence | Comparator | Efficacy |
Harousseau et al. 2010 (IFM 2005-01) | Phase III | autologous hematopoietic cell transplant | Seems not superior |
Treatment preceded by VD x 4 versus VAD x 4.
Chemotherapy
- Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
- Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m2)
- Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m2)
- Cisplatin (Platinol) 15 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 60 mg/m2)
28-day cycle for 2 cycles
All patients then proceeded to receive autologous hematopoietic cell transplant.
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
KTd
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KTd: Kyprolis (Carfilzomib), Thalidomide, dexamethasone
Regimen
Study | Evidence |
Sonneveld et al. 2014 | Phase II |
Treatment preceded by high-dose melphalan with stem cell rescue.
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cohort 1: 27 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
- Cohort 2: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
- Thalidomide (Thalomid) 50 mg PO once per day
- Dexamethasone (Decadron) 20 mg PO once per week on days 1, 8, 15, 22
28-day cycle for 4 cycles
References
- Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. link to original article contains verified protocol PubMed
Lenalidomide & Prednisone
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Regimen
Study | Evidence |
Palumbo et al. 2010 | Phase II |
Treatment preceded by high dose melphalan -> autologous hematopoietic cell transplant.
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Prednisone (Sterapred) 50 mg PO once every other day
Supportive medications
- Aspirin 100 mg PO once per day during Lenalidomide (Revlimid) treatment
28-day cycle for 4 cycles
Treatment followed by lenalidomide maintenance.
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
- 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
Melphalan (Alkeran)
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Regimen
Study | Evidence |
McElwain, Powles 1983 | Pilot Study |
Note that this is highly obsolete but included for historical interest. Stem cell rescue was NOT used.
Chemotherapy
- Melphalan (Alkeran) 100 to 140 mg/m2 IV once
References
- McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983 Oct 8;2(8354):822-4. link to original article PubMed
Melphalan -> autologous hematopoietic cell transplant
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Note that this is incomplete and will be filled in over time.
Regimen
Study | Evidence | Comparator | Efficacy |
Moreau et al. 2002 (IFM 9502) | Phase III | Melphalan & TBI -> autologous transplant | Might have superior OS |
Palumbo et al. 2010 | Phase II | ||
Morgan et al. 2011 (MRC Myeloma IX) | Non-randomized portion of RCT | ||
Moreau et al. 2011 (IFM2007-02) | Non-randomized | ||
Sonneveld et al. 2012 (HOVON-65) | Non-randomized | ||
Lok et al. 2014 | Non-randomized | ||
Roussel et al. 2014 | Phase II | ||
Palumbo et al. 2014 (RV-MM-PI-209) | Phase III | MPR consolidation | Seems to have superior OS |
Sonneveld et al. 2014 | Phase II | ||
Mai et al. 2015 (MM5) | Non-randomized portion of RCT | ||
Mai et al. 2016 (GMMG-HD2) | Phase III | Tandem melphalan -> autoHCT | Seems non-inferior |
Treatment preceded by varying induction regimens:
- IFM 9502: preceded by VAD induction.
- Palumbo et al. 2010: preceded by VDD induction.
- MRC Myeloma IX: preceded by CTD induction versus CVAD induction.
- IFM2007-02: preceded by vtD induction versus VD induction.
- HOVON-65: preceded by PAD induction versus VAD induction.
- Lok et al. 2014: preceded by vtD induction.
- Roussel et al. 2014: preceded by RVD induction.
- RV-MM-PI-209: preceded by RD induction.
- Sonneveld et al. 2014: preceded by KTd induction.
- MM5 preceded by VCD induction versus PAd induction.
Preparative regimen
- Melphalan (Alkeran) 200 mg/m2 IV once on day -2
Stem cells re-infused on day 0
Treatment followed by varying consolidation and/or maintenance regimens:
- IFM 9502: followed by interferon alfa maintenance.
- MRC Myeloma IX: followed by thalidomide maintenance versus no further treatment.
- HOVON-65 was followed by:
- Bortezomib maintenance if patients were induced with PAD, or
- Thalidomide maintenance if they were induced with VAD.
- Lok et al. 2014: followed by vtD consolidation.
- Roussel et al. 2014: followed by RVD consolidation.
- RV-MM-PI-209: followed by lenalidomide maintenance versus no further treatment.
- Sonneveld et al. 2014: followed by KTd consolidation x 4.
- MM5: patients who did not achieve a near CR or better with induction proceeded to a second transplant and then lenalidomide consolidation; others proceeded directly to lenalidomide consolidation.
References
- Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, François S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood. 2002 Feb 1;99(3):731-5. link to original article PubMed
- Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article PubMed
- Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
- Björkstrand B, Iacobelli S, Hegenbart U, Gruber A, Greinix H, Volin L, Narni F, Musto P, Beksac M, Bosi A, Milone G, Corradini P, Goldschmidt H, de Witte T, Morris C, Niederwieser D, Gahrton G. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up. J Clin Oncol. 2011 Aug 1;29(22):3016-22. Erratum in: J Clin Oncol. 2011 Sep 20;29(27):3721. link to original article 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. Epub 2011 Nov 4. link to PMC article contains verified protocol PubMed
- Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-Term Follow-Up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
- Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. 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. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
- Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. link to original article contains verified protocol PubMed
- Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
- Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article contains verified protocol PubMed
- Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. link to original article contains verified protocol PubMed
- Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed
- Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016 Jun;173(5):731-41. Epub 2016 Mar 17. link to original article PubMed
Melphalan -> autoHCT, then RIC alloHCT
Regimen
Study | Evidence |
Garban et al. 2006 (IFM99-03) | Non-randomized |
This regimen was meant for patients who had an HLA-identical sibling donor, and is here for historical interest. Treatment preceded by VAD induction x 4.
Chemotherapy, part 1
- Melphalan (Alkeran) 200 mg/m2 IV on day -2
Stem cells re-infused on day 0
After an interval of 2 months, patients proceeded to allogeneic transplant with busulfan, fludarabine, ATG conditioning.
References
- Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. link to original article contains verified protocol PubMed
- Update: Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM Group. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
MPR
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RP-MPR-RP: Revlimid (Lenalidomide), Prednisone, followed by Melphalan, Prednisone, Revlimid (Lenalidomide), followed by Revlimid (Lenalidomide), Prednisone
Regimen, "RP-MPR-RP"
Study | Evidence |
Falco et al. 2012 | Phase II |
Treatment is preceded by RP induction x 4.
Chemotherapy
- Melphalan (Alkeran) 2 mg PO three times per week
- Prednisone (Sterapred) 50 mg PO three times per week
- Lenalidomide (Revlimid) 10 or 15 mg PO once per day on days 1 to 21
Supportive medications
- Aspirin 100 ?mg PO once per day as thromboprophylaxis during Lenalidomide (Revlimid) treatment. Unclear from protocol if this also means off weeks.
- Antiviral prophylaxis if history of VZV.
28-day cycle for 6 cycles
Treatment is followed by RP maintenance.
References
- Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. link to original article contains verified protocol PubMed
Tandem melphalan -> autologous hematopoietic cell transplant
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To be completed
Regimen #1
Study | Evidence | Comparator | Efficacy |
Gay et al. 2015 | Phase III | CRD consolidation | Superior PFS |
Mai et al. 2016 (GMMG-HD2) | Phase III | Melphalan -> autoHCT | Seems non-inferior |
Treatment preceded by varying induction regimens:
- Gay et al. 2015: preceded by Rd induction x 4.
Chemotherapy
- Melphalan (Alkeran) 200 mg/m2 IV once on day -2
Stem cells re-infused on day 0
Repeated twice
Treatment followed by varying consolidation and/or maintenance regimens:
- Gay et al. 2015: followed by lenalidomide maintenance versus lenalidomide & prednisone maintenance.
Regimen #2
Study | Evidence | Comparator | Efficacy |
Moreau et al. 2005 (IFM99-04) | Phase III | MEL200 -> MEL220 + Dex + B-E8 | Seems not superior |
This regimen was meant for patients who did not have an HLA-identical sibling donor. Treatment preceded by VAD induction x 4.
Chemotherapy, part 1
- Melphalan (Alkeran) 200 mg/m2 IV once on day -2
Stem cells re-infused on day 0
Chemotherapy, part 2
- Melphalan (Alkeran) 220 mg/m2 IV once on day -2
- Dexamethasone (Decadron) 40 mg (route not specified) over 4 days (days not specified)
Stem cells re-infused on day 0
References
- Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. link to original article PubMed
- Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R; InterGroupe Francophone du Myélome. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med. 2003 Dec 25;349(26):2495-502. Erratum in: N Engl J Med. 2004 Jun17;350(25):2628. link to original article PubMed
- Moreau P, Hullin C, Garban F, Yakoub-Agha I, Benboubker L, Attal M, Marit G, Fuzibet JG, Doyen C, Voillat L, Berthou C, Ketterer N, Casassus P, Monconduit M, Michallet M, Najman A, Sotto JJ, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome group.. Tandem autologous stem cell transplantation in high-risk de novo multiple myeloma: final results of the prospective and randomized IFM 99-04 protocol. Blood. 2006 Jan 1;107(1):397-403. Epub 2005 Sep 13. link to original article PubMed
- Update: Garban F, Attal M, Michallet M, Hulin C, Bourhis JH, Yakoub-Agha I, Lamy T, Marit G, Maloisel F, Berthou C, Dib M, Caillot D, Deprijck B, Ketterer N, Harousseau JL, Sotto JJ, Moreau P. Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood. 2006 May 1;107(9):3474-80. Epub 2006 Jan 5. link to original article contains verified protocol PubMed
- Update: Moreau P, Garban F, Attal M, Michallet M, Marit G, Hulin C, Benboubker L, Doyen C, Mohty M, Yakoub-Agha I, Leyvraz S, Casassus P, Avet-Loiseau H, Garderet L, Mathiot C, Harousseau JL; IFM Group. Long-term follow-up results of IFM99-03 and IFM99-04 trials comparing nonmyeloablative allotransplantation with autologous transplantation in high-risk de novo multiple myeloma. Blood. 2008 Nov 1;112(9):3914-5. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
- Bruno B, Rotta M, Patriarca F, Mordini N, Allione B, Carnevale-Schianca F, Giaccone L, Sorasio R, Omedè P, Baldi I, Bringhen S, Massaia M, Aglietta M, Levis A, Gallamini A, Fanin R, Palumbo A, Storb R, Ciccone G, Boccadoro M. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007 Mar 15;356(11):1110-20. link to original article PubMed
- Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. 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. Epub 2012 Jul 16. link to original article PubMed
- Meta-analysis: Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant. 2013 Apr;48(4):562-7. Epub 2012 Sep 10. Review. link to original article PubMed
- Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
- Mai EK, Benner A, Bertsch U, Brossart P, Hänel A, Kunzmann V, Naumann R, Neben K, Egerer G, Ho AD, Hillengass J, Raab MS, Neubauer A, Peyn A, Ko YD, Peter N, Scheid C, Goldschmidt H. Single versus tandem high-dose melphalan followed by autologous blood stem cell transplantation in multiple myeloma: long-term results from the phase III GMMG-HD2 trial. Br J Haematol. 2016 Jun;173(5):731-41. Epub 2016 Mar 17. link to original article PubMed
VTD
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VTD: Velcade (bortezomib), Thalidomide, Dexamethasone
Regimen #1, "vTD"
Study | Evidence |
Lok et al. 2014 | Non-randomized |
Treatment preceded by VTD induction and autologous hematopoietic cell transplantation.
Chemotherapy
- Bortezomib (Velcade) 1 mg/m2 SC once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 100 mg PO once per day
- Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 4
21-day cycle for 2 cycles
Regimen #2
Study | Evidence |
Cavo et al. 2010 | Non-randomized |
Treatment preceded by VTD induction and tandem autologous hematopoietic cell transplant. VTD consolidation is to begin 3 months after the second transplant.
Chemotherapy
- 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
Supportive medications
- Acyclovir (Zovirax) prophylaxis recommended
35-day cycle for 2 cycles
Treatment followed by dexamethasone maintenance.
Regimen #3
Study | Evidence |
Ladetto et al. 2010 (GIMEMA VEL-03-096) | Phase II |
Patients had at least a very good partial response (VGPR) after autologous hematopoietic cell transplantation.
Chemotherapy
- 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 cycle for 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. Epub 2010 Mar 22. link to original article contains verified protocol PubMed
- Update: Ferrero S, Ladetto M, Drandi D, Cavallo F, Genuardi E, Urbano M, Caltagirone S, Grasso M, Rossini F, Guglielmelli T, Cangialosi C, Liberati AM, Callea V, Carovita T, Crippa C, De Rosa L, Pisani F, Falcone AP, Pregno P, Oliva S, Terragna C, Musto P, Passera R, Boccadoro M, Palumbo A. Long-term results of the GIMEMA VEL-03-096 trial in MM patients receiving VTD consolidation after ASCT: MRD kinetics' impact on survival. Leukemia. 2015 Mar;29(3):689-95. Epub 2014 Jul 16. link to original article 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
- Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article contains verified protocol PubMed
- Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous Bortezomib incorporated into the Bortezomib-Thalidomide-Dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. link to original article contains verified protocol PubMed
Maintenance therapy
Note that there is no crisp distinction between consolidation and maintenance. Generally regimens that are intended for a long or indefinite duration would be considered maintenance, whereas regimens with a short intended course would be considered consolidation.
Bortezomib (Velcade)
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Regimen #1
Study | Evidence |
Niesvizky et al. 2015 (UPFRONT) | Non-randomized portion of RCT |
Treatment preceded by VD x 8 versus VMP x 8 versus VTD x 8. All patients received the same maintenance program:
Chemotherapy
- Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22
35-day cycle for 5 cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
Mellqvist et al. 2013 | Phase III | Observation | Might have superior PFS |
This trial only included bortezomib-naive patients; induction regimen was not specified but the majority received Cy-Dex. All patients underwent autologous hematopoietic cell transplant at least 3 months prior to starting maintenance.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
21-day cycle for 2 cycles, then:
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
Supportive medications
- Bisphosphonates were administered "according to national guidelines."
28-day cycle for 4 cycles
Regimen #3
Study | Evidence | Comparator | Efficacy |
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4) | Phase III | Thalidomide | Seems to have superior OS |
Observed efficacy is for induction PAD -> transplant -> maintenance bortezomib compared with induction VAD -> transplant -> maintenance thalidomide. Treatment started 4 weeks after single autologous hematopoietic cell transplant (HOVON-65) or tandem autologous hematopoietic cell transplant (GMMG-HD4).
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once on day 1
14-day cycle for 2 years
Regimen #4
Study | Evidence |
Kumar et al. 2012 (EVOLUTION) | Non-randomized portion of RCT |
Treatment preceded by VDC versus VDC-mod versus VDR versus VDCR.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
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"
42-day cycle for 4 cycles
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
- Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
- Subgroup analysis: Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. link to original article 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. Epub 2013 Apr 24. link to original article contains verified protocol PubMed
- Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article contains verified protocol PubMed
Bortezomib & Prednisone
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Regimen
Study | Evidence | Comparator | Efficacy |
Mateos et al. 2010 (GEM2005) | Phase III | VT | Seems not superior |
Treatment preceded by VMP x 6 versus VTP x 6.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Prednisone (Sterapred) 50 mg PO once every other day
Supportive medications
- Patients with bone disease received bisphosphonates
- Prophylactic aciclovir was recommended.
3-month cycle for up to 3 years
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
- Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
- Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article contains verified protocol PubMed
Carfilzomib (Kyprolis)
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Regimen
Study | Evidence |
Bringhen et al. 2014 | Phase II |
Treatment preceded by CCyd x 9.
Chemotherapy
- 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
- Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. link to original article contains verified protocol PubMed
CRd
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CRd: Carfilzomib, Revlimid (Lenalidomide), (low-dose) dexamethasone
Regimen
Study | Evidence |
Jakubowiak et al. 2012 | Phase II |
This is the MTD dosing in this phase I/II trial. Treatment preceded by CRd x 8 cycles.
Chemotherapy
- Carfilzomib (Kyprolis) 36 mg/m2 IV once per day on days 1, 2, 15, 16
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 20 mg (route not specified) once per week on days 1, 8, 15, 22
28-day cycle for 16 cycles
After a total of 24 cycles (including induction), it was recommended that patients proceed to lenalidomide maintenance.
References
- Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
Dexamethasone (Decadron)
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Regimen
Study | Evidence |
Cavo et al. 2010 | Non-randomized |
Treatment preceded by TD consolidation versus VTD consolidation.
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
Supportive medications
- Acyclovir (Zovirax) prophylaxis recommended
28-day cycles until progression, relapse, or undue toxicity
References
- 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
- Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article contains verified protocol PubMed
- Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, Miranda EC, Quero AA, Peres AL, Barros JC, Tanaka P, Magalhães RP, Rego EM, Lorand-Metze I, Lima CS, Renault IZ, Braggio E, Chiattone C, Nucci M, de Souza CA; Brazilian Multiple Myeloma Study Group (BMMSG/GEMOH). Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012 Oct;87(10):948-52. Epub 2012 Jun 23. link to original article PubMed
Interferon alfa
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Regimen
Study | Evidence | Comparator | Efficacy |
Ludwig et al. 2010 | Phase III | Interferon alfa & Thalidomide | Inferior PFS |
This is of historical interest but is no longer commonly used.
Immunotherapy
References
- Meta-analysis: Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol. 2000 Nov;11(11):1427-36. link to original article PubMed
- Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article contains verified protocol PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
- Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, Spicka I, Gisslinger H, Drach J, Kuhn I, Hinke A, Zojer N. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010 Sep;95(9):1548-54. Epub 2010 Apr 23. link to original article PubMed
Interferon alfa & Thalidomide
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Regimen
Study | Evidence | Comparator | Efficacy |
Ludwig et al. 2010 | Phase III | Interferon alfa | Superior PFS |
This is of historical interest but is no longer commonly used.
Chemotherapy
References
- Ludwig H, Adam Z, Tóthová E, Hajek R, Labar B, Egyed M, Spicka I, Gisslinger H, Drach J, Kuhn I, Hinke A, Zojer N. Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010 Sep;95(9):1548-54. Epub 2010 Apr 23. link to original article PubMed
Ixazomib (Ninlaro)
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Regimen
Study | Evidence |
Kumar et al 2014 | Phase I/II |
Treatment preceded by ixazomib, lenalidomide, dexamethasone x 12 cycles.
Chemotherapy
- Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
28-day cycles until progression
References
- Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A11, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. link to original article PubMed
Lenalidomide (Revlimid)
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Regimen #1, indefinite 10 mg 21/28
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2007 | Phase II | ||
Palumbo et al. 2010 | Phase II | ||
Palumbo et al. 2012 (MM-015) | Phase III | Placebo | Superior PFS |
Palumbo et al. 2014 (RV-MM-PI-209) | Phase III | Observation | Superior PFS |
Stewart et al. 2015 (ECOG E1A06) | Non-randomized portion of RCT | ||
Gay et al. 2015 | Phase III | Lenalidomide & Prednisone | Seems not superior |
Magarotto et al. 2016 (EMN01) | Phase III | Lenalidomide & Prednisone | Not reported |
Zweegman et al. 2016 (HOVON87/NMSG18) | Phase III | Thalidomide | Seems not superior |
Treatment in Palumbo et al. 2007 and MM-015 was preceded by MPR x 9. Treatment in Palumbo et al. 2010 was preceded by lenalidomide & prednisone consolidation. Treatment in RV-MM-PI-209 was preceded by high-dose melphalan with autologous hematopoietic cell transplant versus MPR consolidation. Treatment in ECOG E1A06 was preceded by mPR x 12. Treatment in Gay et al. 2015 preceded by tandem high-dose melphalan with autologous hematopoietic cell transplant versus CRD consolidation. Treatment in EMN01 preceded by CPR x 9 versus MPR x 9 versus Rd x 9. Treatment in HOVON87/NMSG18 preceded by MPR x 9.
Chemotherapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
Supportive medications
- Varies depending on reference:
- Per Palumbo et al. 2010, Aspirin 100 mg PO once per day
- Per ECOG E1A06, Aspirin was required (dose not specified)
- Per ECOG E1A06, full anticoagulation was used for patients at "higher risk" for DVT
- Per ECOG E1A06, Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"
- Per MM-015, Aspirin 75 to 100 mg PO once per day as thromboprophylaxis
- Per Palumbo et al. 2007, Ciprofloxacin (Cipro) 500 mg PO BID and Aspirin 100 mg PO once per day
- Per EMN01, Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
28-day cycles, given until progression or intolerable toxicity
Regimen #2, indefinite 15 mg per day
Study | Evidence | Comparator | Efficacy |
Attal et al. 2012 (IFM 2005-02) | Phase III | Placebo | Superior PFS |
Consolidation
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for 2 cycles, then
Maintenance
- Lenalidomide (Revlimid) 10 mg PO once per day x 3 months, then increased to 15 mg PO once per day if tolerated
Supportive medications
- "Thromboprophylaxis was not used"
Given until progression of disease or unacceptable toxicity, or patient choice
Regimen #3, indefinite 30 mg per day
Study | Evidence | Comparator | Efficacy |
McCarthy et al. 2012 (CALGB 100104) | Phase III | Placebo | Seems to have superior OS |
Patients started therapy 100 to 120 days after autologous hematopoietic cell transplant (AHCT).
Chemotherapy
- 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
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."
Given until progression of disease or unacceptable toxicity
Regimen #4, 2 years of 25 mg 21/28
Study | Evidence |
Korde et al. 2016 | Phase II |
Treatment preceded by CRd x 8.
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for up to 24 cycles
Regimen #5, 1 year of 15 mg per day
Study | Evidence |
Roussel et al. 2014 | Phase II |
Treatment preceded by RVD x 2.
Chemotherapy
- Lenalidomide (Revlimid) 10 mg PO once per day, escalated to 15 mg PO once per day after 3 months, if tolerated.
12-month course
Regimen #6, indefinite 25 mg 21/28
Study | Evidence |
Jakubowiak et al. 2012 | Phase II |
Treatment preceded by CRd x 24.
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles until progression
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, 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
- 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
- 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. 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
- Abstract: Update: Michel Attal, MD, Valerie Cances Lauwers, Gerald Marit, Denis Caillot, Thierry Facon, MD, Cyrille Hulin, Philippe Moreau, MD, Claire Mathiot, Murielle Roussel, Catherine Payen, H. Avet-Loiseau and Jean Luc Harousseau. Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA : Final Analysis of the IFM 2005-02. ASH 2010 Abstract 310. link to abstract
- Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. link to original article contains verified protocol PubMed
- Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article contains verified protocol PubMed
- Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
- Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article contains verified protocol PubMed
- Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article contains verified protocol PubMed
- Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
- Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
- Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed
- Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed
- Abstract: Meta-analysis: Michel Attal, Antonio Palumbo, Sarah A. Holstein, Valerie Lauwers-Cances, Maria Teresa Petrucci, Paul G. Richardson, Cyrille Hulin, Patrizia Tosi, Kenneth Carl Anderson, Denis Caillot, Valeria Magarotto, Philippe Moreau, Gerald Marit, Zhinuan Yu, Philip L. McCarthy. Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): A meta-analysis (MA) of overall survival (OS). J Clin Oncol 34, 2016 (suppl; abstr 8001) link to abstract
- Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. link to original article contains verified protocol PubMed
Lenalidomide & Prednisone
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Magarotto et al. 2016 (EMN01) | Phase III | Lenalidomide | Not reported |
Treatment preceded by CPR x 9 versus MPR x 9 versus Rd x 9.
Chemotherapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
- Prednisone (Sterapred) 25 mg PO once every other day
Supportive medications
- Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
28-day cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
Gay et al. 2015 | Phase III | Lenalidomide | Seems not superior |
Treatment preceded by tandem high-dose melphalan with autologous hematopoietic cell transplant versus CRD consolidation.
Chemotherapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
- Prednisone (Sterapred) 50 mg PO once every other day
28-day cycles
Regimen #3, "RP-MPR-RP"
Study | Evidence |
Falco et al. 2012 | Phase II |
Treatment is preceded by MPR consolidation x 6.
Chemotherapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
- Prednisone (Sterapred) 25 mg PO three times per week
Supportive medications
- Aspirin 100 mg PO once per day as thromboprophylaxis during Lenalidomide (Revlimid) treatment. Unclear from protocol if this also means off weeks.
- Antiviral prophylaxis if history of VZV.
28-day cycles, to continue until relapse, progression, or intolerable side effects
References
- Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. link to original article contains verified protocol PubMed
- Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article contains protocol PubMed
- Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article contains verified protocol PubMed
Observation
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Regimen
Study | Evidence | Comparator | Efficacy |
Attal et al. 2006 (IFM 99-02) | Phase III | Thalidomide | Inferior OS |
Morgan et al. 2012 (MRC Myeloma IX) | Phase III | Thalidomide | Inferior PFS |
Attal et al. 2012 (IFM 2005-02) | Phase III | Lenalidomide | Inferior PFS |
McCarthy et al. 2012 (CALGB 100104) | Phase III | Lenalidomide | Seems to have inferior OS |
Stewart et al. 2013 (NCICCTG Myeloma 10 Trial) | Phase III | Thalidomide & Prednisone | Inferior PFS |
Mellqvist et al. 2013 | Phase III | Bortezomib | Might have inferior PFS |
Palumbo et al. 2014 (GIMEMA RV-209) | Phase III | Lenalidomide | Inferior PFS |
No treatment or placebo; used as a comparator arm.
References
- Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
- Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article 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 PubMed
- Abstract: Update: Michel Attal, MD, Valerie Cances Lauwers, Gerald Marit, Denis Caillot, Thierry Facon, MD, Cyrille Hulin, Philippe Moreau, MD, Claire Mathiot, Murielle Roussel, Catherine Payen, H. Avet-Loiseau and Jean Luc Harousseau. Maintenance Treatment with Lenalidomide After Transplantation for MYELOMA : Final Analysis of the IFM 2005-02. ASH 2010 Abstract 310. link to abstract
- 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. link to original article link to supplementary appendix PubMed
- Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013 Feb 28;121(9):1517-23. Epub 2013 Jan 7. link to original article 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. Epub 2013 Apr 24. link to original article PubMed
- Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article PubMed
Prednisone
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Berenson et al. 2002 (SWOG 9210) | Phase III | Low-dose prednisone | Seems to have superior OS |
Treatment preceded by VAD-P versus VAD-P/Q.
Chemotherapy
- Prednisone (Sterapred) 50 mg PO once every other day
Given until disease progression
Regimen #2
Study | Evidence | Comparator | Efficacy |
Berenson et al. 2002 (SWOG 9210) | Phase III | High-dose prednisone | Seems to have inferior OS |
Treatment preceded by #VAD-P versus VAD-P/Q.
Chemotherapy
- Prednisone (Sterapred) 10 mg PO once every other day
Given 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
- Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009 Apr 10;27(11):1788-93. Epub 2009 Mar 9. link to original article PubMed
RVD
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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
Regimen #1
Study | Evidence |
Roussel et al. 2014 | Phase II |
Treatment preceded by autologous hematopoietic cell transplant. Two months after hematologic recovery, patients without progressive disease received:
Chemotherapy
- 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
Supportive medications
- Low–molecular weight heparin (LMWH) for DVT prophylaxis
- Antiviral therapy with example valacyclovir given, for herpes zoster prevention
- Antibiotic prophylaxis with example amoxicillin given, for bacterial infections
21-day cycle for 2 cycles
Patients then proceeded to receive lenalidomide maintenance.
Regimen #2
Study | Evidence |
Richardson et al. 2010 | Phase II |
Treatment preceded by RVD x 4 to 8 cycles.
Chemotherapy
- 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
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
21-day cycles until progression or intolerance
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
- Nooka AK, Kaufman JL, Muppidi S, Langston A, Heffner LT, Gleason C, Casbourne D, Saxe D, Boise LH, Lonial S. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014 Mar;28(3):690-3. Epub 2013 Nov 13. link to original article PubMed
- Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article contains verified protocol PubMed
Thalidomide (Thalomid)
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2006 | Non-randomized | ||
Stewart et al. 2015 (ECOG E1A06) | Non-randomized portion of RCT | ||
Zweegman et al. 2016 (HOVON87/NMSG18) | Phase III | Lenalidomide | Seems not superior |
Treatment in Palumbo et al. 2006 preceded by MPT x 6. Treatment in ECOG E1A06 preceded by MPT x 12. Treatment in HOVON87/NMSG18 preceded by MPT x 9.
Chemotherapy
- Thalidomide (Thalomid) 100 mg PO once per day
Supportive medications
- Per ECOG E1A06, Aspirin was required (dose not specified)
- Per ECOG E1A06, full anticoagulation was used for patients at "higher risk" for DVT
- Per ECOG E1A06, Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"
Continued until evidence of relapse or refractory disease
Regimen #2
Study | Evidence | Comparator | Efficacy |
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4) | Phase III | Bortezomib | Seems to have inferior OS |
Observed efficacy is for induction PAD -> transplant -> maintenance bortezomib compared with induction VAD -> transplant -> maintenance thalidomide. Treatment preceded by single autologous hematopoietic cell transplant (HOVON-65) or tandem autologous hematopoietic cell transplant (GMMG-HD4). Treatment starts 4 weeks after autologous hematopoietic cell transplant.
Chemotherapy
- Thalidomide (Thalomid) 50 mg PO once per day
2-year course
Regimen #3
Study | Evidence | Comparator | Efficacy |
Morgan et al. 2012 (MRC Myeloma IX) | Phase III | Observation | Superior PFS |
Treatment preceded by autologous hematopoietic cell transplant in the intensive treatment pathway; treatment preceded by CTDa versus MP in the nonintensive treatment pathway.
Chemotherapy
- Thalidomide (Thalomid) as follows:
- Weeks 1 to 4: 50 mg PO once per day
- Week 5 onwards: 100 mg PO once per day
Continued until progression
Regimen #4
Study | Evidence | Comparator | Efficacy |
Attal et al. 2006 (IFM 99-02) | Phase III | Observation | Superior OS |
Treatment preceded by VAD x 3 to 4 and tandem autologous hematopoietic cell transplant.
Chemotherapy
- Thalidomide (Thalomid) 400 mg PO once per day
- Dose reductions to a minimum of 50 mg PO once per day were allowed
Continued until progression
Regimen #5
Study | Evidence |
Wijermans et al. 2010 (HOVON 49) | Non-randomized |
Treatment preceded by MPT x 8.
Chemotherapy
- Thalidomide (Thalomid) 50 mg PO once per day
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."
- During maintenance therapy, "low-dose Aspirin was advised"
Continued until progression
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
- 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
- Sahebi F, Spielberger R, Kogut NM, Fung H, Falk PM, Parker P, Krishnan A, Rodriguez R, Nakamura R, Nademanee A, Popplewell L, Frankel P, Ruel C, Tin R, Ilieva P, Forman SJ, Somlo G. Maintenance thalidomide following single cycle autologous peripheral blood stem cell transplant in patients with multiple myeloma. Bone Marrow Transplant. 2006 May;37(9):825-9. link to original article PubMed
- Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; Inter-Groupe Francophone du Myélome (IFM). Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006 Nov 15;108(10):3289-94. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
- Update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the intergroupe francophone du myelome, southwest oncology group, and university of arkansas for medical sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article PubMed
- **RETRACTED** Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, Romdhane NB, Omri HE, Elloumi M, Belaaj H, Jeddi R, Aissaouï L, Ksouri H, Hassen AB, Msadek F, Saad A, Hsaïri M, Boukef K, Amouri A, Louzir H, Dellagi K, Abdeladhim AB; Tunisian Multiple Myeloma Study Group. Single autologous stem-cell transplantation followed by maintenance therapy with thalidomide is superior to double autologous transplantation in multiple myeloma: results of a multicenter randomized clinical trial. Blood. 2008 Feb 15;111(4):1805-10. Epub 2007 Sep 17. link to original article contains verified protocol PubMed **RETRACTED**
- Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. link to original article contains verified protocol PubMed
- Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. 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. Epub 2012 Jul 16. link to original article contains verified protocol PubMed
- Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article contains verified protocol link to PMC article PubMed
- Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article contains verified protocol PubMed
Thalidomide & Dexamethasone
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Regimen
Study | Evidence | Comparator | Efficacy |
Maiolino et al. 2012 | Phase III | Dexamethasone | Superior PFS |
Treatment preceded by high-dose melphalan & autologous hematopoietic cell transplant.
Chemotherapy
- Thalidomide (Thalomid) 200 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, every 28 days
12 months or until disease progression
References
- Maiolino A, Hungria VT, Garnica M, Oliveira-Duarte G, Oliveira LC, Mercante DR, Miranda EC, Quero AA, Peres AL, Barros JC, Tanaka P, Magalhães RP, Rego EM, Lorand-Metze I, Lima CS, Renault IZ, Braggio E, Chiattone C, Nucci M, de Souza CA; Brazilian Multiple Myeloma Study Group (BMMSG/GEMOH). Thalidomide plus dexamethasone as a maintenance therapy after autologous hematopoietic stem cell transplantation improves progression-free survival in multiple myeloma. Am J Hematol. 2012 Oct;87(10):948-52. Epub 2012 Jun 23. link to original article contains verified protocol PubMed
Thalidomide & Prednisone
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Regimen
Study | Evidence | Comparator | Efficacy | Toxicity |
Stewart et al. 2013 (NCICCTG Myeloma 10 Trial) | Phase III | Observation | Improved PFS | Decreased QOL |
Treatment preceded by autologous hematopoietic cell transplant.
Chemotherapy
- Thalidomide (Thalomid) 200 mg PO once per day
- Prednisone (Sterapred) 50 mg PO once every other day
Supportive medications
- "Bisphosphonates, histamine-2 blockers, and laxatives were recommended"
- "Anticoagulant and antiplatelet medications were not mandated"
Four years or until disease progression
References
- Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009 Apr 10;27(11):1788-93. Epub 2009 Mar 9. link to original article PubMed
- Stewart AK, Trudel S, Bahlis NJ, White D, Sabry W, Belch A, Reiman T, Roy J, Shustik C, Kovacs MJ, Rubinger M, Cantin G, Song K, Tompkins KA, Marcellus DC, Lacy MQ, Sussman J, Reece D, Brundage M, Harnett EL, Shepherd L, Chapman JA, Meyer RM. A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013 Feb 28;121(9):1517-23. Epub 2013 Jan 7. link to original article contains verified protocol PubMed
VT
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VT: Velcade (Bortezomib), Thalidomide
Regimen #1
Study | Evidence | Comparator | Efficacy |
Mateos et al. 2010 (GEM2005) | Phase III | Bortezomib & Prednisone | Seems not superior |
Treatment preceded by VMP x 6 versus VTP x 6.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Thalidomide (Thalomid) 50 mg PO once per day
Supportive medications
- Patients with bone disease received bisphosphonates
- Prophylactic aciclovir was recommended.
- Thromboprophylaxis with either aspirin or low molecular weight heparin
3-month cycle for up to 3 years
Regimen #2
Study | Evidence |
Palumbo et al. 2010 | Non-randomized |
Treatment preceded by VMPT x 9.
Chemotherapy
- 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 cycle for 2 years or until disease progression or relapse
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
- Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article PubMed
- Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. 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. Epub 2010 Oct 12. link to original article contains verified protocol PubMed
- Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article contains verified protocol PubMed
- Subset analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article PubMed
- Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article contains verified protocol PubMed
Relapsed/refractory, randomized data
BD; Bort-Dex
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BD: Bortezomib, Dexamethasone
Bd: Bortezomib, low-dose dexamethasone
Bort-Dex: Bortezomib, Dexamethasone
Vd: Velcade (Bortezomib), low-dose dexamethasone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Jakubowiak et al. 2016 | Randomized Phase II | EBd | Might have inferior PFS |
Chemotherapy
- Bortezomib (Velcade) as follows:
- Cycles 1 to 8: 1.3 mg/m2 SC/IV once per day on days 1, 4, 8, 11
- Cycle 9 onwards: 1.3 mg/m2 SC/IV once per day on days 1, 8, 15
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
- Cycle 9 onwards: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16
21-day cycle for 8 cycles, then 28-day cycles
Regimen #2
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2016 (CASTOR) | Phase III | DVd | Inferior PFS |
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 SC 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 cycle for 8 cycles
Regimen #3
Study | Evidence | Comparator | Efficacy |
San-Miguel et al. 2014 (PANORAMA 1) | Phase III | Bortezomib, Dexamethasone, Panobinostat | Inferior PFS |
Phase 1
- 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 cycle for 8 cycles
Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to phase 2 treatment:
Phase 2
- Bortezomib (Velcade) 1.3 mg/m2 IV once per week days 1, 8, 22, 29
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30
6-week cycle for 4 cycles
Regimen #4
Study | Evidence | Comparator | Efficacy |
Hjorth et al. 2012 | Phase III | Thal-Dex | Superior VGPR rate |
Dimopoulos et al. 2013 | Phase II |
Chemotherapy
- 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
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."
21-day cycles, to be continued until progression or best response, which would then be followed by 1 to 2 additional cycles
References
- Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains 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. Epub 2012 Mar 30. link to PMC 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 Aug;98(8):1264-72. Epub 2013 May 28. link to original article contains verified protocol PubMed
- San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. link to original article contains verified protocol PubMed
- Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article PubMed
- Update: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Oct 14. [Epub ahead of print] link to original article PubMed
- Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. link to original article PubMed
- Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. link to original article contains verified protocol in supplement PubMed
- Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed
Bortezomib (Velcade)
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Orlowski et al. 2015 | Randomized Phase II | Bortezomib & Siltuximab | Seems not superior |
Chemotherapy, part 1
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32
42-day cycle for up to 4 cycles, followed by:
Chemotherapy, part 2
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
35-day cycles until progression
Regimen #2
Study | Evidence | Comparator | Efficacy |
Richardson et al. 2003 (SUMMIT) | Phase II | ||
Jagannath et al. 2004 (CREST) | Randomized Phase II | Low-dose Bortezomib +/- Dexamethasone | Seems not superior |
Moreau et al. 2011 (MMY-3021) | Phase III | Subcutaneous Bortezomib +/- Dexamethasone | Non-inferior ORR |
Note: MMY-3021 allowed for up to 10 cycles of treatment; SUMMIT and CREST allowed up to 8 cycles.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
- Patients in 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 per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycle for 8 to 10 cycles
Regimen #3
Study | Evidence | Comparator | Efficacy |
Richardson et al. 2005 (APEX) | Phase III | High-dose dexamethasone | Superior OS |
Chemotherapy, part 1
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
21-day cycle for 8 cycles, followed by:
Chemotherapy, part 2
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
35-day cycle for 3 cycles
Supportive medications
- Bisphosphonate IV therapy once every 3 to 4 weeks unless contraindicated
Regimen #4, SC bortezomib +/- dexamethasone
Study | Evidence | Comparator | Efficacy |
Moreau et al. 2011 (MMY-3021) | Phase III | Intravenous Bortezomib +/- Dexamethasone | Non-inferior ORR |
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 SC 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
- 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 per day on days 1, 2, 4, 5, 8, 9, 11, 12
Supportive medications
- Bisphosphonates "according to established guidelines"
21-day cycle for 8 to 10 cycles
Regimen #5, indefinite 21-day cycles
Study | Evidence | Comparator | Efficacy |
Orlowski et al. 2007 | Phase III | Bortezomib & Doxorubicin liposomal | Inferior TTP |
Dimopoulos et al. 2013 (VANTAGE 088) | Phase III | Bortezomib & Vorinostat | Seems to have inferior PFS |
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
21-day cycles until progression or intolerance
Regimen #6
Study | Evidence | Comparator | Efficacy |
Jagannath et al. 2004 (CREST) | Randomized Phase II | Bortezomib +/- Dexamethasone | Seems not superior |
Chemotherapy
- Bortezomib (Velcade) 1 mg/m2 IV bolus once per day on days 1, 4, 8, 11
- 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 per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycle for 8 cycles
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
- Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
- Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. link to original article contains verified protocol PubMed
- Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains protocol PubMed
- Update: Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. link to original article 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
- Update: 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
- 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
- Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. link to original article contains 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. Epub 2012 Jun 11. link to original article PubMed
- Subgroup analysis: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. Epub 2015 Jan 16. link to original article PubMed
- Petrucci MT, Giraldo P, Corradini P, Teixeira A, Dimopoulos MA, Blau IW, Drach J, Angermund R, Allietta N, Broer E, Mitchell V, Bladé J. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013 Mar;160(5):649-59. Epub 2013 Jan 7. link to original article PubMed
- Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. Epub 2013 Sep 19. link to original article contains verified protocol PubMed
- Orlowski RZ, Gercheva L, Williams C, Sutherland H, Robak T, Masszi T, Goranova-Marinova V, Dimopoulos MA, Cavenagh JD, Špička I, Maiolino A, Suvorov A, Bladé J, Samoylova O, Puchalski TA, Reddy M, Bandekar R, van de Velde H, Xie H, Rossi JF. A phase 2, randomized, double-blind, placebo-controlled study of siltuximab (anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol. 2015 Jan;90(1):42-9. link to PMC article contains verified protocol PubMed
Bortezomib, Dexamethasone, Panobinostat
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Regimen
Study | Evidence | Comparator | Efficacy |
Richardson et al. 2013 (PANORAMA 2) | Phase II | ||
San-Miguel et al. 2014 (PANORAMA 1) | Phase III | Bortezomib & Dexamethasone | Increased PFS |
Phase 1
- 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
- Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12
21-day cycle for 8 cycles
Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to phase 2 treatment:
Phase 2
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 22, 29
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 22, 23, 29, 30
- Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12, 22, 24, 26, 29, 31, 33
6-week cycles
Patients in PANORAMA 1 received 4 cycles; PANORAMA 2 continued treatment until progression of disease, unacceptable toxicity, or death.
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 Oct 3;122(14):2331-7. link to original article contains verified protocol PubMed
- San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. link to original article contains verified protocol PubMed
- Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article PubMed
- Update: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Oct 14. [Epub ahead of print] link to original article PubMed
Bortezomib & Doxorubicin liposomal
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Regimen
Study | Evidence | Comparator | Efficacy |
Orlowski et al. 2007 | Phase III | Bortezomib | Superior TTP |
Chemotherapy
- 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 (Velcade)
Supportive medications
- Bisphosphonates were used according to established guidelines
21-day cycle for up to 8 cycles
Treatment given until progression of disease, or unacceptable toxicity; treatment could be continued beyond 8 cycles if it was tolerated.
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
Bortezomib & Vorinostat
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Regimen
Study | Evidence | Comparator | Efficacy |
Dimopoulos et al. 2013 (VANTAGE 088) | Phase III | Bortezomib | Seems to have superior PFS |
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
- Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 14
21-day cycles
References
- Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. Epub 2013 Sep 19. link to original article contains verified protocol PubMed
BTD
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BTD: Bendamustine, Thalidomide, Dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Schey et al. 2015 (MUKone) | Randomized Phase II | BTD with higher-dose benadmustine | Not reported |
This study involved two doses of bendamustine but the higher dose was too toxic. Dosage listed is the lower dose.
Chemotherapy
- Bendamustine 60 mg/m2 IV once per day on days 1 & 8
- Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21 (**Note: abstract says days 1 to 21 but body of paper says days 1 to 28**)
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22
Supportive medications
- Thromboprophylaxis (not specified)
- Anti-infective prophylaxis (not specified)
28-day cycle for 6 to 9 cycles (2 cycles past best response)
References
- Schey S, Brown SR, Tillotson AL, Yong K, Williams C, Davies F, Morgan G, Cavenagh J, Cook G, Cook M, Orti G, Morris C, Sherratt D, Flanagan L, Gregory W, Cavet J; Myeloma UK Early Phase Clinical Trial Network. Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial. Br J Haematol. 2015 Aug;170(3):336-48. Epub 2015 Apr 20. link to original article contains verified protocol PubMed
Carfilzomib & Dexamethasone
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Regimen
Study | Evidence | Comparator | Efficacy |
Dimopoulos et al. 2015 (ENDEAVOR) | Phase III | Bortezomib & Dexamethasone | Superior PFS |
To be completed; abstract with insufficient details
Chemotherapy
References
- Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. link to original article PubMed
CRd; KRd
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CRd: Carfilzomib, Revlimid (Lenalidomide), (low-dose) dexamethasone
KRd: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), (low-dose) dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Stewart et al. 2014 (ASPIRE) | Phase III | Rd | Superior PFS |
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV over 10 minutes once per day on days 1 & 2, then 27 mg/m2 IV over 10 minutes once per day on days 8, 9, 15, 16
- Cycles 2 to 12: 27 mg/m2 IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
- Cycles 13 to 18: 27 mg/m2 IV over 10 minutes once per day on days 1, 2, 15, 16
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
Supportive medications
- Valacyclovir (Valtrex) (dose not specified) or equivalent antiviral while taking Lenalidomide (Revlimid)
- Aspirin (dose not specified) or other anticoagulant or antiplatelet medication such as Clopidogrel (Plavix), low-molecular-weight heparin or Warfarin (Coumadin) while taking Lenalidomide (Revlimid)
- Bisphosphonates while taking Dexamethasone (Decadron)
- Lansoprazole (Prevacid) (dose not specified) or other proton pump inhibitor while taking Dexamethasone (Decadron)
- A prophylactic antibiotic (Ciprofloxacin (Cipro), Amoxicillin, Trimethoprim/Sulfamethoxazole (Bactrim DS) are given as examples)
28-day cycles until progression or intolerable side effects (Carfilzomib stopped after 18 cycles)
References
- Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed
- Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article PubMed
Dexamethasone (Decadron)
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Regimen #1
Study | Evidence | Comparator | Efficacy |
San Miguel et al. 2013 (MM-003) | Phase III | PD | Inferior PFS |
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
28-day cycles until disease progression or unacceptable toxicity
Regimen #2
Study | Evidence | Comparator | Efficacy |
Weber et al. 2007 (MM-009) | Phase III | RD | Seems to have inferior OS |
Dimopoulos et al. 2007 (MM-010) | Phase III | RD | Seems to have inferior OS |
Chemotherapy
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycle 5 onwards: 40 mg PO once per day on days 1 to 4
28-day cycles until progression or intolerable side effects
Regimen #3, "LoDEX"
Study | Evidence | Comparator | Efficacy |
Richardson et al. 2014 | Randomized Phase II | POM+LoDEX (PD) | Seems to have inferior PFS |
Chemotherapy
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
Supportive medications
- Aspirin 81 to 100 mg per day unless contraindicated
28-day cycles until disease progression or unacceptable toxicity
References
- 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 PubMed
- Update: 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 PubMed
- 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
- Update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article 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
- Update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article PubMed
- San Miguel J, 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 Oct;14(11):1055-66. Epub 2013 Sep 3. link to original article contains verified protocol PubMed
- Update: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. link to original article PubMed
- Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol PubMed
DRd
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DRd: Daratumumab, Revlimid (Lenalidomide), (low-dose) dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Plesner et al. 2016 | Phase I/II | ||
Dimpoulos et al. 2016 (POLLUX) | Phase III | Rd | Superior PFS |
Chemotherapy
- Daratumumab (Darzalex) as follows:
- Cycles 1 & 2: 16 mg/kg IV once per week
- Cycles 3 to 6: 16 mg/kg IV once every two weeks
- Cycle 7 onwards: 16 mg/kg IV once per cycle
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- POLLUX: Patients with CrCl of 30 to 60 ml/min received 10 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
- POLLUX: Patients older than 75 years or underweight (BMI <18.5) could receive 20 mg PO once per week
28-day cycle for up to 24 months (Plesner et al. 2014) or until progression (POLLUX)
References
- Plesner T, Arkenau HT, Gimsing P, Krejcik J, Lemech C, Minnema MC, Lassen U, Laubach JP, Palumbo A, Lisby S, Basse L, Wang J, Sasser AK, Guckert ME, de Boer C, Khokhar NZ, Yeh H, Clemens PL, Ahmadi T, Lokhorst HM, Richardson PG. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016 Oct 6;128(14):1821-8. Epub 2016 Aug 16. link to original article contains verified protocol PubMed
- Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators.. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol contains verified protocol PubMed
DVd
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DVd: Daratumumab, Velcade (Bortezomib), low-dose dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Palumbo et al. 2016 (CASTOR) | Phase III | Vd | Superior PFS |
Chemotherapy
- Daratumumab (Darzalex) as follows:
- Cycles 1 to 3: 16 mg/kg IV once per week
- Cycles 4 to 8: 16 mg/kg IV once on day 1
- Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 20 mg PO/IV once per day on days 1, 2, 4, 5, 8, 9, 11, 12
- Can be dose-reduced to 20 mg PO/IV once per week for patients > 75 years, with BMI < 18.5, or with previous side effects
21-day cycle for 8 cycles
Treatment followed by daratumumab maintenance.
References
- Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed
EBd
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EBd: Elotuzumab, Bortezomib, low-dose dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Jakubowiak et al. 2016 | Randomized Phase II | Bd | Might have superior PFS |
Chemotherapy
- Elotuzumab (Empliciti) as follows:
- Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15
- Cycles 3 to 8: 10 mg/kg IV once per day on days 1 & 11
- Cycle 9 onwards: 10 mg/kg IV once per day on days 1 & 15
- Bortezomib (Velcade) as follows:
- Cycles 1 to 8: 1.3 mg/m2 SC/IV once per day on days 1, 4, 8, 11
- Cycle 9 onwards: 1.3 mg/m2 SC/IV once per day on days 1, 8, 15
- Dexamethasone (Decadron) as follows:
- Cycles 1 & 2:
- 20 mg PO once per day on days 2, 4, 5, 9, 11, 12
- 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1, 8, 15
- Cycles 3 to 8:
- 20 mg PO once per day on days 2, 4, 5, 8, 9, 12
- 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1 & 11
- Cycle 9 onwards:
- 20 mg PO once per day on days 2, 8, 9, 16
- 8 mg PO 3 to 24 hours prior and 8 mg IV 45 minutes prior to Elotuzumab (Empliciti) on days 1 & 15
- Cycles 1 & 2:
Supportive medications
- Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) 30 to 90 minutes prior to Elotuzumab (Empliciti)
- Ranitidine (Zantac) 50 mg (route not specified) 30 to 90 minutes prior to Elotuzumab (Empliciti)
- Acetaminophen (Tylenol) 650 to 1000 mg PO 30 to 90 minutes prior to Elotuzumab (Empliciti)
21-day cycle for 8 cycles, then 28-day cycles
References
- Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. link to original article contains verified protocol in supplement PubMed
Elotuzumab, Lenalidomide, Dexamethasone
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Regimen #1
Study | Evidence | Comparator | Efficacy |
Lonial et al. 2015 (ELOQUENT-2) | Phase III | Lenalidomide & Dexamethasone | Superior PFS |
Richardson et al. 2015 (1703 Study) | Randomized Phase Ib/II | Elotuzumab 20 mg, Lenalidomide, Dexamethasone | Seems not superior |
Note: the complex dexamethasone instructions for ELOQUENT-2 were not described in the abstract of Richardson et al. 2015.
Chemotherapy
- Elotuzumab (Empliciti) as follows:
- Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
- Cycle 3 onwards: 10 mg/kg IV once per day on days 1 & 15
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week on weeks without elotuzumab; 28 mg PO and 8 mg IV on days when Elotuzumab (Empliciti) is administered
- According to the elotuzumab package insert, the 28 mg PO dose should be given between 3 and 24 hours before elotuzumab; the 8 mg IV dose should be given 45 to 90 minutes before elotuzumab.
Supportive medications
- Mandatory premedications 30 to 90 minutes prior to Elotuzumab (Empliciti):
- Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) or its equivalent
- Ranitidine (Zantac) 50 mg (route not specified) or its equivalent
- Acetaminophen (Tylenol) 650 to 1000 mg (route not specified) or its equivalent
- "Thromboembolic prophylaxis (e.g., aspirin, low-molecular-weight heparin, or vitamin K antagonists) was administered according to institutional guidelines or at the discretion of the investigator."
28-day cycles, given until progression of disease or unacceptable toxicity
Regimen #2
Study | Evidence | Comparator | Efficacy |
Richardson et al. 2015 (1703 Study) | Randomized Phase Ib/II | Elotuzumab 10 mg, Lenalidomide, Dexamethasone | Seems not superior |
Chemotherapy
- Elotuzumab (Empliciti) as follows:
- Cycles 1 & 2: 20 mg/kg IV once per day on days 1, 8, 15, 22
- Cycle 3 onwards: 20 mg/kg IV once per day on days 1 & 15
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week
28-day cycles, given until progression of disease or unacceptable toxicity
References
- Phase I: Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012 Jun 1;30(16):1953-9. link to original article contains verified protocol PubMed
- Abstract: Update: Paul G. Richardson, Sundar Jagannath, MD, Philippe Moreau, MD, Andrzej Jakubowiak, MD, PhD, Marc S Raab, MD, PhD, Thierry Facon, MD, Ravi Vij, MBBS, MD, Darrell White, MD, Donna E. Reece, MD, Lotfi Benboubker, MD, PhD, Jeffrey Zonder, MD, L. Claire Tsao, PhD, Kenneth C. Anderson, MD, Eric Bleickardt, MD, Anil K Singhal, MD and Sagar Lonial, MD. Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma. ASH 2014 Abstract 302 link to abstract
- Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. link to original article contains verified protocol PubMed
- Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, Zonder J, Tsao LC, Anderson KC, Bleickardt E, Singhal AK, Lonial S; 1703 study investigators. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015 Dec;2(12):e516-27. Epub 2015 Nov 16. link to original article contains protocol PubMed
IRd
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IRd: Ixazomib, Revlimid (Lenalidomide), low-dose dexamethasone
Regimen
Study | Evidence | Comparator |
Moreau et al. 2016 (TOURMALINE-MM1) | Phase III | Rd |
Chemotherapy
- Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15, taken at least one hour before or at least two hours after food
- Lenalidomide (Revlimid) as follows:
- Normal renal function: 25 mg PO once per day on days 1 to 21
- CrCl of ≤60 or ≤50 (depends on local practice): 10 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
Supportive medications
- Thromboprophylaxis required
28-day cycles, given until progression of disease or unacceptable toxicity
References
- Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. link to original article contains verified protocol PubMed
Lenalidomide (Revlimid)
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Regimen
Study | Evidence | Comparator | Efficacy |
Richardson et al. 2006 | Randomized Phase II | Lenalidomide 15 mg PO BID | Seems not superior |
Richardson et al. 2009 | Phase II |
This regimen is essentially of historical interest, as neither dosing of lenalidomide is in common use now.
Chemotherapy
- Lenalidomide (Revlimid) 30 mg PO once per day on days 1 to 21
28-day cycles
Patients in Richardson et al. 2006 with SD or progression after 2 cycles were escalated to RD.
References
- Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, Williams SF, Bensinger W, Badros AZ, Vescio R, Kenvin L, Yu Z, Olesnyckyj M, Zeldis J, Knight R, Anderson KC. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009 Jul 23;114(4):772-8. Epub 2009 May 26. link to original article contains verified protocol PubMed
- Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article link to PMC article contains verified protocol PubMed
PD
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PD: Pomalidomide, Dexamethasone
PomDex: Pomalidomide, Dexamethasone
Pom + LoDEX: Pomalidomide, Low-dose Dexamethasone
Regimen #1
Study | Evidence | Comparator | Efficacy |
San Miguel et al. 2013 (MM-003) | Phase III | Dexamethasone | Superior PFS |
Leleu et al. 2013 (IFM 2009-02) | Randomized Phase II | Pom-Dex (28/28) | Seems not superior |
Richardson et al. 2014 | Randomized Phase II | LoDEX (Dexamethasone) | Seems to have superior PFS |
Leleu et al. 2015 (IFM 2010-02) | Phase II | ||
Baz et al. 2016 | Randomized Phase I/II | PomCyDex | Seems to have inferior ORR rate |
Dimopoulos et al. 2016 (STRATUS) | Phase IIIb |
Chemotherapy
- Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) as follows:
- Age ≤75: 40 mg PO once per day on days 1, 8, 15, 22
- Age >75: 20 mg PO once per day on days 1, 8, 15, 22
Supportive medications
- San 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"
- Richardson et al. 2014: Aspirin 81 to 100 mg once per day unless contraindicated
- Baz et al. 2016: Aspirin 81 mg once per day unless contraindicated
- STRATUS: Thromboprophylaxis with low-dose Aspirin, LMWH, or equivalent was required
- Leleu et al. 2013: G-CSF allowed beginning with cycle 2 and on
28-day cycles until disease progression or unacceptable toxicity
Regimen #2
Study | Evidence | Comparator | Efficacy |
Lacy et al. 2011 | Phase II | ||
Leleu et al. 2013 (IFM 2009-02) | Randomized phase II, >20 patients | Pom-Dex (21/28) | Seems not superior |
Chemotherapy
- Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 28
- Dexamethasone (Decadron) 40 mg PO once per day on day 1, 8, 15, 22
Supportive medications
- Lacy et al. 2011: Aspirin 325 mg PO once per day; low molecular weight heparin or Warfarin (Coumadin) could be substituted at physician discretion
- Leleu et al. 2013: Thromboprophylaxis "at the physician's discretion"
- Leleu et al. 2013: G-CSF allowed beginning with cycle 2 and on
28-day cycles until disease progression or unacceptable toxicity
References
- Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011 Sep 15;118(11):2970-5. Epub 2011 Jun 20. link to original article contains verified protocol PubMed
- 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
- San Miguel J, 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 Oct;14(11):1055-66. Epub 2013 Sep 3. link to original article contains verified protocol PubMed
- Update: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. link to original article PubMed
- Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article contains verified protocol PubMed
- Leleu X, Karlin L, Macro M, Hulin C, Garderet L, Roussel M, Arnulf B, Pegourie B, Kolb B, Stoppa AM, Brechiniac S, Marit G, Thielemans B, Onraed B, Mathiot C, Banos A, Lacotte L, Tiab M, Dib M, Fuzibet JG, Petillon MO, Rodon P, Wetterwald M, Royer B, Legros L, Benboubker L, Decaux O, Escoffre-Barbe M, Caillot D, Fermand JP, Moreau P, Attal M, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome (IFM). Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015 Feb 26;125(9):1411-7. Epub 2015 Jan 9. link to original article contains verified protocol PubMed
- Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article contains verified protocol PubMed
- Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, Weisel KC, Oriol A, Hansson M, Vacca A, Blanchard MJ, Goldschmidt H, Doyen C, Kaiser M, Petrini M, Anttila P, Cafro AM, Raymakers R, San-Miguel J, de Arriba F, Knop S, Röllig C, Ocio EM, Morgan G, Miller N, Simcock M, Peluso T, Herring J, Sternas L, Zaki MH, Moreau P. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016 Jul 28;128(4):497-503. Epub 2016 May 25. link to original article contains verified protocol PubMed
PomCyDex
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PomCyDex: Pomalidomide, Cyclophosphamide, Dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Baz et al. 2016 | Randomized Phase I/II | PomDex | Seems to have superior ORR rate |
Chemotherapy
- Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
- Cyclophosphamide (Cytoxan) 400 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 40 mg (20 mg for patients >75 years old) PO once per day on days 1, 8, 15, 22
Supportive medications
- Aspirin 81 mg once per day unless contraindicated
28-day cycles until disease progression or unacceptable toxicity
References
- Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article contains verified protocol PubMed
RD; Rd
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RD: Revlimid (Lenalidomide), Dexamethasone
Rd: Revlimid (Lenalidomide), (low-dose) dexamethasone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Stewart et al. 2014 (ASPIRE) | Phase III | KRd | Inferior PFS |
Moreau et al. 2016 (TOURMALINE-MM1) | Phase III | IRd | Inferior PFS |
Dimpoulos et al. 2016 (POLLUX) | Phase III | DRd | Inferior PFS |
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- POLLUX: Patients with CrCl of 30 to 60 ml/min received 10 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
- POLLUX: Patients older than 75 years or underweight (BMI <18.5) could receive 20 mg PO once per week
Supportive medications
Best described by ASPIRE:
- Valacyclovir (Valtrex) (dose not specified) or equivalent antiviral while taking Lenalidomide (Revlimid)
- Aspirin (dose not specified) or other anticoagulant or antiplatelet medication such as Clopidogrel (Plavix), low-molecular-weight heparin or Warfarin (Coumadin) while taking Lenalidomide (Revlimid)
- Bisphosphonates while taking Dexamethasone (Decadron)
- Lansoprazole (Prevacid) (dose not specified) or other proton pump inhibitor while taking Dexamethasone (Decadron)
- A prophylactic antibiotic (Ciprofloxacin (Cipro), Amoxicillin, Trimethoprim/Sulfamethoxazole (Bactrim DS) are given as examples)
28-day cycles until progression or intolerable side effects
Regimen #2
Study | Evidence | Comparator | Efficacy |
Weber et al. 2007 (MM-009) | Phase III | Dexamethasone | Seems to have superior OS |
Dimopoulos et al. 2007 (MM-010) | Phase III | Dexamethasone | Seems to have superior OS |
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
- Cycle 5 onwards: 40 mg PO once per day on days 1 to 4
28-day cycles until progression or intolerable side effects
Regimen #3
Study | Evidence | Comparator | Efficacy |
Richardson et al. 2006 | Randomized Phase II | Dexamethasone & twice-daily Lenalidomide | Seems not superior |
This regimen is essentially of historical interest, and was preceded by lenalidomide monotherapy x 2 cycles.
Chemotherapy
- Lenalidomide (Revlimid) 30 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 15 to 18
28-day cycles until progression
References
- Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article link to PMC article contains verified protocol PubMed
- 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
- Update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article 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
- Update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article PubMed
- Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Spicka I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; the ASPIRE Investigators. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article contains verified protocol PubMed
- Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article PubMed
- Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. link to original article PubMed
- Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral Ixazomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. link to original article contains verified protocol PubMed
- Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators.. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol contains verified protocol PubMed
TD; Thal-Dex
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TD: Thalidomide, Dexamethasone
Thal-Dex: Thalidomide, Dexamethasone
Regimen #1
Study | Evidence | Comparator | Efficacy |
Garderet et al. 2012 (MMVAR/IFM 2005-04) | Phase III | VTD | Inferior TTP |
Intended for patients who have relapsed after an autologous stem-cell transplant
Chemotherapy
- Thalidomide (Thalomid) 200 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of a 21-day cycle
Supportive medications
- Enoxaparin (Lovenox) 40 mg SC once per day for primary prophylaxis; Warfarin (Coumadin) for secondary prophylaxis
One year of treatment
Regimen #2
Study | Evidence | Comparator | Efficacy |
Hjorth et al. 2012 | Phase III | Bort-Dex | Inferior VGPR rate |
Chemotherapy
- 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
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."
21-day cycles, to be continued until progression or best response, which would then be followed by 1 to 2 additional cycles
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. Epub 2012 Mar 30. link to PMC article contains verified protocol PubMed
- Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. link to original article contains verified protocol PubMed
VTD
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VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone
Regimen
Study | Evidence | Comparator | Efficacy |
Garderet et al. 2012 (MMVAR/IFM 2005-04) | Phase III | TD | Superior TTP |
Intended for patients who have relapsed after an autologous stem-cell transplant
Chemotherapy
- Bortezomib (Velcade) as follows:
- Cycles 1 to 8: 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11 of a 21-day cycle
- Cycles 9 to 12: 1.3 mg/m2 IV bolus once per week on days 1, 8, 15, 22 of a 42-day cycle
- Thalidomide (Thalomid) 200 mg PO once per day
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4 of a 21-day cycle
Supportive medications
- Enoxaparin (Lovenox) 40 mg SC once per day for primary prophylaxis; Warfarin (Coumadin) for secondary prophylaxis
- Herpes zoster prophylaxis highly recommended
One year of treatment
References
- Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. link to original article contains verified protocol PubMed
Relapsed/refractory, non-randomized or retrospective data
BBD
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BBD: Bendamustine, Bortezomib, Dexamethasone
Regimen
Study | Evidence |
Ludwig et al. 2013 | Phase II |
Chemotherapy
- Bendamustine 70 mg/m2 IV once per day on days 1 & 4
- Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) 20 mg (route not specified) once per day on days 1, 4, 8, 11
28-day cycle for up to 8 cycles
References
- Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Weißmann A, Adam Z. Bendamustine-bortezomib-dexamethasone is an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014 Feb 13;123(7):985-91. Epub 2013 Nov 13. link to original article contains verified protocol PubMed
BD; Bort-Dex
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BD: Bortezomib, Dexamethasone
Bort-Dex: Bortezomib, Dexamethasone
Regimen
Study | Evidence |
Fukushima et al. 2011 | Phase II |
Chemotherapy
- 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
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
BLD
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BLD: Bendamustine, Lenalidomide, Dexamethasone
Regimen
Study | Evidence |
Lentzsch et al. 2012 | Phase I/II |
Dosages listed are the determined maximally tolerated doses (MTD) of this phase I/II trial.
Chemotherapy
- Bendamustine 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
Supportive medications
- Aspirin 325 mg PO once per day
- "Gastroprotectant" (H2-blocker or PPI)
28-day cycle for up to 8 cycles
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. Epub 2012 Mar 26. link to original article contains verified protocol PubMed
Bortezomib (Velcade)
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Regimen
Study | Evidence |
Hainsworth et al. 2008 | Phase II |
Chemotherapy
- Bortezomib (Velcade) 1.6 mg/m2 IV bolus once per day on days 1, 8, 15, 22
35-day cycle for up to 10 cycles
References
- Hainsworth JD, Spigel DR, Barton J, Farley C, Schreeder M, Hon J, Greco FA. Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer. 2008 Aug 15;113(4):765-71. link to original article contains verified protocol PubMed
Bortezomib, Cyclophosphamide, Dexamethasone
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Regimen #1
Study | Evidence |
de Waal et al. 2015 | Phase II |
Treatment intended for bortezomib-naive patients.
Chemotherapy
- Bortezomib (Velcade) as follows:
- Cycles 1 to 3: 1.3 mg/m2 IV/SC once per day on days 1, 4, 8, 11
- Cycles 4 to 6: 1.6 mg/m2 IV/SC once per day on days 1, 8, 15, 22
- Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
- Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
Supportive medications
- Pneumococccal and anti-fungal prophylaxis "according to local protocols"
- Valacyclovir (Valtrex) (dose not specified) for herpes prophylaxis
21-day cycle for 3 cycles then 35-day cycle for 3 cycles
Patients with PR/CR after 6 cycles proceeded to bortezomib & cyclophosphamide maintenance.
Regimen #2
Study | Evidence |
Kropff et al. 2007 | Phase II |
Treatment intended for bortezomib-naive patients.
Chemotherapy
- Bortezomib (Velcade) as follows:
- Cycles 1 to 3: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
- Cycles 4 to 6: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
- Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
- Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
21-day cycle for 3 cycles then 35-day cycle for 3 cycles
References
- Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom,. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007 Aug;138(3):330-7. link to original article contains verified protocol PubMed
- de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article contains verified protocol PubMed
Carfilzomib (Kyprolis)
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Regimen #1, 20/27 dosing, variant #1
Study | Evidence |
Watanabe et al. 2016 | Phase I/II |
This is the maximum predetermined dose, there was no MTD.
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 27 mg/m2 IV once per day on days 8, 9, 15, 16
- Cycle 2 onwards: 27 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
Supportive medications
- IV and PO hydration required for cycle 1, then as needed
- Dexamethasone (Decadron) 4 mg PO/IV prior to each cycle 1 dose, then as needed
- Prophylactic antibiotics (not specified) in cycle 1
- Acyclovir (Zovirax) for patients with history of herpes infection, in cycle 1
28-day cycles until progression or excess toxicity
Regimen #2, 20/56 dosing
Study | Evidence |
Lendvai et al. 2014 | Phase II |
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV over 30 minutes once per day on days 1 & 2, then 56 mg/m2 IV over 30 minutes once per day on days 8, 9, 15, 16
- Cycle 2 onwards: 56 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16
Supportive medications
- Normal saline pre- and post-hydration, tapered over subsequent cycles (see text for details)
- Dexamethasone (Decadron) 8 mg (route not specified) mandated with each cycle 1 dose, then optional
- Palonosetron (Aloxi) 250 mcg (route not specified) mandated with each cycle 1 dose, then optional
- Acyclovir (Zovirax) 400 mg PO once per day
Regimen #3, 20/27 dosing, variant #2
Study | Evidence |
Vij et al. 2012 (PX-171-004) | Phase II |
Siegel et al. 2012 (PX-171-003-A1) | Phase II |
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
- Cycle 2 onwards: 27 mg/m2 (body surface area capped at 2.2 m2) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 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%."
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 modifications
- "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."
28-day cycle for up to 12 cycles, given until progression of disease or unacceptable toxicity
Regimen #4, 20 dosing
Study | Evidence |
Jagannath et al. 2012 (PX-171-003-A0) | Phase II |
As described in the abstract, this variant does not include dose escalation or BSA capping.
Chemotherapy
- Carfilzomib (Kyprolis) 20 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
28-day cycle for up to 12 cycles
Regimen #5, 15/20/27 dosing, for renal impairment
Study | Evidence |
Badros et al. 2013 (PX-171-005) | Phase II |
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 15 mg/m2 IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
- Cycle 2: 20 mg/m2 IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
- Cycle 3 onwards: 27 mg/m2 IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
Supportive medications
- Dexamethasone (Decadron) 4 mg (route not specified) before all doses in cycle 1. Continue dexamethasone premedication if patients experience "treatment-related fever, chills, and/or dyspnea."
- "All patients were "required to be well hydrated."
28-day cycle for 12 cycles or longer if deriving clinical benefit
Patients with less than PR after 2 cycles or less than CR after 4 cycles were allowed to receive Dexamethasone (Decadron) 20 mg prior to each dose of carfilzomib.
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
- Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S, Wong AF, Wang M. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012 Sep;158(6):739-48. Epub 2012 Jul 30. link to original article PubMed
- Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. link to original article contains 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
- Subset analysis: Jakubowiak AJ, Siegel DS, Martin T, Wang M, Vij R, 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, Harrison BL, Wong AF, Orlowski RZ, Jagannath S. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013 Dec;27(12):2351-6. Epub 2013 May 14. link to original article PubMed
- Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. link to PMC article contains verified protocol PubMed
- Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, Giralt SA. A phase 2 single-center study of carfilzomib 56 mg/m2 with or without low-dose dexamethasone in relapsed multiple myeloma. Blood. 2014 Aug 7;124(6):899-906. Epub 2014 Jun 24. link to original article contains verified protocol PubMed
- Watanabe T, Tobinai K, Matsumoto M, Suzuki K, Sunami K, Ishida T, Ando K, Chou T, Ozaki S, Taniwaki M, Uike N, Shibayama H, Hatake K, Izutsu K, Ishikawa T, Shumiya Y, Kashihara T, Iida S. A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma. Br J Haematol. 2016 Mar;172(5):745-56. Epub 2016 Jan 5. link to original article contains verified protocol PubMed
Carfilzomib & Dexamethasone
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Regimen
Study | Evidence |
Berenson et al. 2016 (CHAMPION-1) | Phase I/II |
The carfilzomib dose is the MTD in this phase I/II trial.
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV over 30 minutes once on day 1, then 70 mg/m2 IV over 30 minutes once per day on days 8 & 15
- Cycle 2 onwards: 70 mg/m2 IV once per day on days 1, 8, 15
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 8: 40 mg PO/IV once per day on days 1, 8, 15, 22
- Cycle 9 onwards: 40 mg PO/IV once per day on days 1, 8, 15
28-day cycles until progression or intolerance
References
- Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016 Jun 30;127(26):3360-8. Epub 2016 May 12. link to original article contains verified protocol PubMed
Carfilzomib & Panobinostat
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Regimen
Study | Evidence |
Berdeja et al. 2015 | Phase II |
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once on days 1 & 2, then 45 mg/m2 IV over 30 minutes once per day on days 8, 9, 15, 16
- Cycle 2 onwards: 45 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
- Panobinostat (Farydak) 30 mg PO once per day on days 1, 3, 5, 15, 17, 19
28-day cycles until progression or intolerance
References
- Berdeja JG, Hart LL, Mace JR, Arrowsmith ER, Essell JH, Owera RS, Hainsworth JD, Flinn IW. Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. Haematologica. 2015 May;100(5):670-6. Epub 2015 Feb 20. link to PMC article link to original article contains verified protocol PubMed
CPD; KPD
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CPD: Carfilzomib, Pomalidomide, Dexamethasone
KPD: Kyprolis (Carfilzomib), Pomalidomide, Dexamethasone
Regimen
Study | Evidence |
Shah et al. 2015 | Phase I (*) |
Note, although this is described as a Phase I trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV over 30 minutes once per day on days 1 & 2, then 27 mg/m2 IV over 30 minutes once per day on days 8, 9, 15, 16
- Cycles 2 to 6: 27 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16
- Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 4: 40 mg PO/IV once per week on days 1, 8, 15, 22
- Cycles 5 to 6: 20 mg PO/IV once per week on days 1, 8, 15, 22
Supportive medications
- "Anti-viral therapy"
- Aspirin 81 mg PO once per day
- Low molecular weight heparin was used in patients intolerant of aspirin
28-day cycle for 6 cycles or until disease progression, or unacceptable toxicity
Treatment followed by maintenance CPD.
References
- Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. link to original article link to PMC article contains verified protocol PubMed
CPR; REP
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CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)
REP: Revlimid (Lenalidomide), Endoxan (Cyclophosphamide), Prednisone
Regimen #1, "REP"
Study | Evidence |
Nijhof et al. 2016 (REPEAT) | Phase I/II |
Details are for the MTD/phase II portion of the published phase I/II trial.
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Cyclophosphamide (Cytoxan) 50 mg PO once per day
- Prednisone (Sterapred) 20 mg PO once per day
28-day cycles
Regimen #2, "CPR"
Study | Evidence |
Reece et al. 2014 | Phase I/II |
Details are for the phase II portion of the published phase I/II trial.
Chemotherapy
- Cyclophosphamide (Cytoxan) 300 mg/m2 PO on days 1, 8, 15
- Prednisone (Sterapred) 100 mg PO once every other day
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles
References
- Reece DE, Masih-Khan E, Atenafu EG, Jimenez-Zepeda VH, Anglin P, Chen C, Kukreti V, Mikhael JR, Trudel S. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma. Br J Haematol. 2015 Jan;168(1):46-54. Epub 2014 Aug 22. link to original article contains protocol PubMed
- Nijhof IS, Franssen LE, Levin MD, Bos GM, Broijl A, Klein SK, Koene HR, Bloem AC, Beeker A, Faber LM, van der Spek E, Ypma PF, Raymakers R, van Spronsen DJ, Westerweel PE, Oostvogels R, van Velzen J, van Kessel B, Mutis T, Sonneveld P, Zweegman S, Lokhorst HM, van de Donk NW. Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma. Blood. 2016 Sep 19. [Epub ahead of print] link to original article contains verified protocol PubMed
CRd; KRd
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CRd: Carfilzomib, Revlimid (Lenalidomide), (low-dose) dexamethasone
KRd: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), (low-dose) dexamethasone
Regimen
Study | Evidence |
Wang et al. 2013 | Phase II |
Chemotherapy
- Carfilzomib (Kyprolis) as follows:
- Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 27 mg/m2 IV once per day on days 8, 9, 15, 16
- Cycles 2 to 12: 27 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
- Cycles 13 to 18: 27 mg/m2 IV once per day on days 1, 2, 15, 16
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 40 mg PO once per week on days 1, 8, 15, 22
28-day cycle for up to 18 cycles, longer duration allowed at discretion of investigator
Patients with at least SD after 4 cycles received up to 12 cycles; patients with at least SD after 12 cycles received up to 18 cycles.
References
- Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, Huang M, Orlowski RZ, Niesvizky R. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013 Oct 31;122(18):3122-8. Epub 2013 Sep 6. link to original article contains verified protocol PubMed
CTD
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CTD: Cyclophosphamide, Thalidomide, Dexamethasone
Regimen
Study | Evidence |
Dimopoulos et al. 2004 | Phase II |
Chemotherapy
- Cyclophosphamide (Cytoxan) 150 mg/m2 PO every 12 hours (before meals) on days 1 to 5
- Thalidomide (Thalomid) as follows:
- Cycles 1 to 3: 400 mg PO every evening on days 1 to 5 and 14 to 18
- Cycle 4 onwards: 400 mg PO every evening on days 1 to 5
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 3: 20 mg PO every morning after breakfast on days 1 to 5 and 14 to 18
- Cycle 4 onwards: 20 mg PO every morning after breakfast on days 1 to 5
28-day cycles
References
- Dimopoulos MA, Hamilos G, Zomas A, Gika D, Efstathiou E, Grigoraki V, Poziopoulos C, Xilouri I, Zorzou MP, Anagnostopoulos N, Anagnostopoulos A. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J. 2004;5(2):112-7. PubMed
Daratumumab (Darzalex)
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Regimen
Study | Evidence |
Lokhorst et al. 2015 (GEN501 part 2) | Phase I/II |
Lonial et al. 2016 (SIRIUS) | Phase II |
Note: although SIRIUS was a randomized phase II trial, the randomization was to choose the dose for further assessment in an expansion cohort; the dose chosen (16 mg/kg from the start) is the one reported here:
Chemotherapy
- Daratumumab (Darzalex) as follows:
- Weeks 1 to 8: 16 mg/kg IV once per week
- Weeks 9 to 24: 16 mg/kg IV once every 2 weeks
- Weeks 25 and on: 16 mg/kg IV once every 4 weeks
- Per the package insert, daratumumab infusion should complete within 15 hours. In Lokhorst et al. 2015, daratumumab was given over 8 hours.
Supportive medications
This is a combination of what is listed in the daratumumab package insert and Lokhorst et al. 2015. There were protocol amendments in Lokhorst et al. 2015; listed medications are what was eventually used.
- Prior to all daratumumab infusions:
- Methylprednisolone (Solumedrol) 100 mg IV prior to every dose of daratumumab. Per the package insert, after the second dose of daratumumab, methylprednisolone may be reduced to 60 mg IV. Per Lokhorst et al. 2015, after the fourth dose of daratumumab, methylprednisolone "could be reduced to 50 mg."
- Acetaminophen (Tylenol) (paracetamol) 1000 mg (package insert: 650 to 1000 mg) PO 1 to 2 hours prior to daratumumab
- Antihistamine: clemastine 1 mg IV, Cetirizine (Zyrtec) 10 mg PO, Diphenhydramine (Benadryl) 25 to 50 mg PO/IV, or equivalent 1 to 2 hours prior to daratumumab
- Post-treatment medications:
- Methylprednisolone (Solumedrol) 20 to 25 mg (package insert: 20 mg) PO or equivalent one and two days after every daratumumab infusion
- Package insert: "For patients with a history of obstructive pulmonary disorder, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids."
- Package insert: "Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting DARZALEX and continue for 3 months following treatment"
Given until progression of disease or unacceptable toxicity
References
- Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. link to original article contains verified protocol link to supplementary appendix link to study protocol PubMed
- Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. Epub 2016 Jan 7. link to original article contains protocol PubMed
- Pooled update: Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. Epub 2016 May 23. link to original article link to PMC article PubMed
DCEP
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DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol (Cisplatin)
Regimen #1
Study | Evidence |
Lazzarino et al. 2001 | Phase II |
Note: this protocol is reported as a mobilization regimen prior to high dose autologous transplant; all patients had received prior therapy.
Chemotherapy
- Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
- Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m2)
- Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m2)
- Cisplatin (Platinol) 10 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 40 mg/m2)
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 48 hours after chemotherapy and continuing through stem cell collection
One course
Regimen #2
Study | Evidence |
Dadacaridou et al. 2007 | Phase II, <20 patients reported |
These limited details are based on the abstract's description only. Full article was not available for review.
Chemotherapy
- Dexamethasone (Decadron) 40 mg IV bolus once per day on days 1 to 4
- Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 1600 mg/m2)
- Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 160 mg/m2)
- Cisplatin (Platinol) 15 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 60 mg/m2)
Supportive medications
- G-CSF SC once per day, starting on day 5, to continue until neutrophil recovery
28-day cycles
References
- Lazzarino M, Corso A, Barbarano L, Alessandrino EP, Cairoli R, Pinotti G, Ucci G, Uziel L, Rodeghiero F, Fava S, Ferrari D, Fiumanò M, Frigerio G, Isa L, Luraschi A, Montanara S, Morandi S, Perego D, Santagostino A, Savarè M, Vismara A, Morra E. DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) is an effective regimen for peripheral blood stem cell collection in multiple myeloma. Bone Marrow Transplant. 2001 Nov;28(9):835-9. link to original article contains verified protocol 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. PubMed
DTPACE
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DTPACE: Dexamethasone, Thalidomide, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide
Regimen
Study | Evidence |
Lee et al. 2003 | Prospective |
To be completed
References
- Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, van Rhee F, Cottler-Fox M, Muwalla F, Tricot G. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003 Jul 15;21(14):2732-9. Erratum in: J Clin Oncol. 2008 Apr 20;26(12): 2066. link to original article PubMed
Hyper-CVAD
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Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone
Regimen
Study | Evidence |
Dimopoulos et al. 1996 | Phase II |
To be completed
References
- Dimopoulos MA, Weber D, Kantarjian H, Delasalle KB, Alexanian R. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol. 1996 Jun;52(2):77-81. link to original article PubMed
Ixazomib (Ninlaro)
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Regimen
Study | Evidence |
Kumar et al 2015 | Phase II |
Chemotherapy
- Ixazomib (Ninlaro) 5.5 mg PO once per day on days 1, 8, 15
28-day cycles until progression
Patients with no minor response by end of cycle 2, no PR by end of cycle 4, or progression proceeded to receive ixazomib & dexamethasone.
References
- Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. link to original article contains verified protocol PubMed
Ixazomib & Dexamethasone
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Regimen
Study | Evidence |
Kumar et al 2015 | Phase II |
Chemotherapy
- Ixazomib (Ninlaro) 5.5 mg PO once per day on days 1, 8, 15
- Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16
28-day cycles until progression
References
- Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. link to original article contains verified protocol PubMed
PAD
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PAD: PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
Note that this regimen is sometimes called VAD but this can create a lot of confusion with the "original" VAD which uses Vincristine.
VAD: Velcade (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
Regimen
Study | Evidence |
Cook et al. 2016 (BSBMT/UKMF Myeloma X) | Non-randomized portion of RCT |
Note: length of cycle is not reported in the abstract, but presumably is 28 days, similar to other PAD regimens.
Chemotherapy
- 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) as follows:
- Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18
- Cycles 2 to 4: 40 mg PO once per day on days 1 to 4
4 cycles
Patients were then randomized to high-dose melphalan & autologous hematopoietic cell transplant versus weekly oral cyclophosphamide.
References
- Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. link to original article contains protocol PubMed
PCP
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PCP: Pomalidomide, Cyclophosphamide, Prednisone
Regimen
Study | Evidence |
Larocca et al. 2013 | Phase I/II |
Details are for the phase II portion of the published phase I/II trial.
Chemotherapy
- Pomalidomide (Pomalyst) 2.5 mg PO once per day
- Cyclophosphamide (Cytoxan) 50 mg PO once every other day
- Prednisone (Sterapred) 50 mg PO once every other day
Supportive medications
- Aspirin 100 mg PO once per day or low-molecular-weight heparin "according to patient risk"
28-day cycle for 6 cycles
Treatment followed by pomalidomide & prednisone maintenance.
References
- Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article contains verified protocol PubMed
PD
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PD: Pomalidomide, Dexamethasone
Regimen
Study | Evidence |
Lacy et al. 2009 | Phase II |
Lacy et al. 2010 | Phase II |
Lacy et al. 2011 | Phase II |
Chemotherapy
- Pomalidomide (Pomalyst) 2 mg PO once per day on days 1 to 28
- Dexamethasone (Decadron) 40 mg PO once per day on day 1, 8, 15, 22
Supportive medications
- Aspirin 325 mg PO once per day; low molecular weight heparin or Warfarin (Coumadin) could be substituted at physician discretion
28-day cycles given until disease progression or unacceptable toxicity
References
- Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009 Oct 20;27(30):5008-14. Epub 2009 Aug 31. link to original article contains verified protocol PubMed
- Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010 Nov;24(11):1934-9. Epub 2010 Sep 9. link to original article contains verified protocol PubMed
- Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011 Sep 15;118(11):2970-5. Epub 2011 Jun 20. link to original article contains verified protocol PubMed
RVD
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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
Regimen
Study | Evidence |
Richardson et al. 2014 | Phase II |
Chemotherapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
- Bortezomib (Velcade) 1.0 mg/m2 IV once per day on days 1, 4, 8, 11
- Dexamethasone (Decadron) as follows:
- Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
- Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
Supportive medications
21-day cycle for 8 cycles
Patients who had at least stable disease and tolerated therapy could proceed to maintenance RVD at previously tolerated dose.
References
- Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. link to original article contains verified protocol PubMed
Thalidomide (Thalomid)
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Regimen
Study | Evidence |
Singhal et al. 1999 | Non-randomized |
Chemotherapy
- Thalidomide (Thalomid) 200 mg PO once per day, increased by 200 mg every two weeks for six weeks, to final dose of 800 mg per day
Continued until progression
References
- Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. Erratum in: N Engl J Med 2000 Feb 3;342(5):364. link to original article contains protocol PubMed
Vemurafenib (Zelboraf)
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Regimen
Study | Evidence |
Andrulis et al. 2013 | Case report |
Note that Andrulis et al. 2013 is a single patient case report with a good response. Sharman et al. reports two patients with good response. In the Hyman et al. 2015 trial, there were 5 patients with multiple myeloma; "No patients with multiple myeloma have had a response to date."
Chemotherapy
- Vemurafenib (Zelboraf) 480 mg PO BID for one week, then increased to 720 mg PO BID
References
- Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, Zenz T, von Deimling A, Schirmacher P, Ho AD, Goldschmidt H, Neben K, Raab MS. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013 Aug;3(8):862-9. Epub 2013 Apr 23. link to original article contains protocol PubMed
- Sharman JP, Chmielecki J, Morosini D, Palmer GA, Ross JS, Stephens PJ, Stafl J, Miller VA, Ali SM. Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014 Oct;14(5):e161-3. Epub 2014 Jun 11. link to original article PubMed
- Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med. 2015 Aug 20;373(8):726-36. link to original article PubMed
VMPT
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VMPT: Velcade (Bortezomib), Melphalan, Prednisone, Thalidomide
Regimen
Study | Evidence |
Palumbo et al. 2007 | Phase II |
Chemotherapy
- 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 cycle for 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
Consolidation after salvage therapy
Melphalan -> autologous hematopoietic cell transplant
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Regimen
Study | Evidence | Comparator | Efficacy |
Cook et al. 2016 (BSBMT/UKMF Myeloma X) | Phase III | Cyclophosphamide | Seems to have superior OS |
Treatment preceded by PAD x 4.
Preparative regimen
- Melphalan (Alkeran) 200 mg/m2 IV on day -2
Stem cells re-infused on day 0
References
- Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. link to original article contains protocol PubMed
Maintenance after salvage therapy
Bortezomib & Cyclophosphamide
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Regimen
Study | Evidence |
de Waal et al. 2015 | Phase II |
Treatment preceded by bortezomib, cyclophosphamide, dexamethasone x 6.
Chemotherapy
- Bortezomib (Velcade) 1.3 mg/m2 IV/SC every 2 weeks
- Cyclophosphamide (Cytoxan) 50 mg PO once per day (continuous)
Supportive medications
- Pneumococccal and anti-fungal prophylaxis "according to local protocols"
- Valacyclovir (Valtrex) (dose not specified) for herpes prophylaxis
1-year course
References
- de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article contains verified protocol PubMed
CPD; KPD
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CPD: Carfilzomib, Pomalidomide, Dexamethasone
KPD: Kyprolis (Carfilzomib), Pomalidomide, Dexamethasone
Regimen
Study | Evidence |
Shah et al. 2015 | Phase I (*) |
Note, although this is described as a Phase I trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here. Treatment preceded by CPD x 6.
Chemotherapy
- Carfilzomib (Kyprolis) 27 mg/m2 IV over 30 minutes once per day on days 1, 2, 15, 16
- Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
- Dexamethasone (Decadron) 20 mg PO/IV once per week on days 1, 8, 15, 22
Supportive medications
- "Anti-viral therapy"
- Aspirin 81 mg PO once per day
- Low molecular weight heparin was used in patients intolerant of aspirin
28-day cycles, given until disease progression, or unacceptable toxicity
References
- Phase I: Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. link to original article link to PMC article contains verified protocol PubMed
Daratumumab (Darzalex)
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Regimen
Study | Evidence |
Palumbo et al. 2016 (CASTOR) | Non-randomized portion of RCT |
Treatment preceded by DVd x 8.
Chemotherapy
- Daratumumab (Darzalex) 16 mg/kg IV once on day 1
4-week cycles until progression
References
- Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix contains verified protocol PubMed
Pomalidomide & Prednisone
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Regimen
Study | Evidence |
Larocca et al. 2013 | Phase I/II |
Details are for the phase II portion of the published phase I/II trial. Treatment preceded by PCP x 6.
Chemotherapy
- Pomalidomide (Pomalyst) 1 mg PO once per day
- Prednisone (Sterapred) 25 mg PO once every other day
Supportive medications
- Aspirin 100 mg PO once per day or low-molecular-weight heparin "according to patient risk"
Continuously until any signs of relapse or progression
References
- Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article contains verified protocol PubMed
RVD
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RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
Regimen
Study | Evidence |
Richardson et al. 2014 | Phase II |
Treatment preceded by salvage RVD.
Chemotherapy
- Lenalidomide (Revlimid) (at previously tolerated dose) PO once per day on days 1 to 14
- Bortezomib (Velcade) (at previously tolerated dose) IV once per day on days 1 & 8
- Dexamethasone (Decadron) 10 mg PO once per day on days 1, 2, 8, 9
Supportive medications
21-day cycles until progression or intolerance
References
- Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. link to original article contains verified protocol PubMed
Investigational agents
These are drugs under study with at least some promising results for this disease.
- Afuresertib (GSK2110183)
- Dinaciclib (SCH 727965)
- Perifosine (KRX-0401)
- Ricolinostat (ACY-1215, Rocilinostat)
Response criteria
- IMWG international uniform response criteria for multiple myeloma. (Durie et al. Leukemia 2006) PubMed
- Make note of these errors which remain in the online version of the IMWG criteria as of 7/7/2013.
- Clarification of the definition of complete response in multiple myeloma (Leukemia 2015) PubMed
- Disease progression criteria (Durie et al. Leukemia 2006).
- European Blood and Marrow Transplant (EBMT) criteria. (Bladé et al. Br J Hematol 1998) PubMed
Prognosis
Durie-Salmon Staging System - 1975
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Composed of four factors with a modifier based on renal function
- Serum levels of monoclonal protein (only defined for IgM, IgA, and Bence-Jones)
- Number of lytic bone lesions
- Hemoglobin
- Serum calcium level
Risk stratification
- Stage I: (must meet ALL criteria)
- Hemoglobin >10 g/dL
- Calcium normal or ≤12 mg/dL
- Skeletal survey with normal bone structure (scale 0) or solitary bone plasmacytoma only
- Monoclonal protein relatively small (IgG M-spike value <5 g/dL OR IgA M-spike value <3 g/dL OR urine light chain protein <4 g/24 hr)
- Stage II: not stage I or stage III
- Stage III: (if meets ANY of the criteria)
- Hemoglobin <8.5 g/dL
- Calcium >12 mg/dL
- Skeletal survey with extensive skeletal destruction and major fractures
- Monoclonal protein relatively large (IgG M-spike value >7 g/dL OR IgA M-spike value >5 g/dL OR urine light chain protein >12 g/24 hr)
Modifier
- A: relatively normal creatinine (<2 mg/dL)
- B: creatinine ≥2 mg/dL
References
- 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. link to original article PubMed
International Staging System (ISS) - 2005
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Composed of two factors
- Serum albumin level
- Serum beta-2 microglobulin level
Risk stratification
- Stage I: Median survival of 62 months
- Beta-2 microglobulin <3.5 mg/l
- Albumin ≤3.5 g/dl
- Stage II: Median survival of 44 months
- Not meeting stage I or stage III criteria
- Stage III: Median survival of 29 months
- Beta-2 microglobulin ≥5.5 mg/l
References
- 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. Epub 2008 Oct 30. link to PMC article PubMed
IMWG consensus on risk stratification - 2013
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Composed of four factors
- Serum albumin level
- Serum beta-2 microglobulin level
- Age
- Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)
Risk stratification
- Low risk: (must meet all criteria) Median survival of > 10 years
- ISS Stage I or II
- Age < 55 years
- Absence of the following: del(17p13), t(4;14), +1q21
- Standard risk: Median survival of 7 years
- Not meeting low risk or high risk criteria
- High risk: (if meets both criteria) Median survival of 2 years
- ISS Stage II or III
- Either of the following: del(17p13) or t(4;14)
References
- Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, Miguel JS, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H; International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014 Feb;28(2):269-77. Epub 2013 Aug 26. Review. link to original article PubMed
Revised International Staging System (R-ISS) - 2015
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Composed of four factors
- Serum albumin level
- Serum beta-2 microglobulin level
- Serum LDH
- Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)
Risk stratification
- Low risk: 5-year overall survival = 82%
- Beta-2 microglobulin <3.5 mg/l
- Albumin ≤3.5 g/dl
- LDH less than the upper limit of normal range
- Absence of the following: del(17p), t(4;14), t(14;16)
- Intermediate risk: 5-year overall survival = 62%
- Not meeting low risk or high risk criteria
- High risk: (if meets ANY of the criteria) 5-year overall survival = 40%
- Beta-2 microglobulin ≥5.5 mg/l
- LDH greater than the upper limit of normal range
- Any of the following: del(17p), t(4;14), t(14;16)
References
- Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-9. Epub 2015 Aug 3. link to original article
Miscellaneous
- Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007 Apr 15;109(8):3489-95. Epub 2007 Jan 5. link to original article PubMed
- Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M, Royer B, Dib M, Voillat L, Bouscary D, Caillot D, Wetterwald M, Pegourie B, Lepeu G, Corront B, Karlin L, Stoppa AM, Fuzibet JG, Delbrel X, Guilhot F, Kolb B, Decaux O, Lamy T, Garderet L, Allangba O, Lifermann F, Anglaret B, Moreau P, Harousseau JL, Facon T. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the intergroupe francophone du myélome experience. J Clin Oncol. 2013 Aug 1;31(22):2806-9. Epub 2013 Jun 24. link to original article PubMed