Multiple myeloma - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. Is there a regimen missing from this list? Please go to the main multiple myeloma regimen page to find other regimens.
Last updated on 2024-09-06:50 regimens on this page
91 variants on this page
 
=First-line therapy=
==ABCM==
ABCM: Adriamycin (Doxorubicin), BCNU (Carmustine), Cyclophosphamide, Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
MacLennan et al. 1992 (MRC Myeloma V)	1982-1986 	Phase 3 (E-esc)	Melphalan 	Longer OSMedian OS: 32 vs 24 mo
Child et al. 2003 (MRC Myeloma VII) 	1993-2000 	Phase 3 (C) 	C-VAMP 	Seems to have shorter OS
====Chemotherapy====
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
*Carmustine (BCNU) 30 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 22 to 25
*Melphalan (Alkeran) 6 mg/m2 PO once per day on days 22 to 25
42-day cycle for varying durations: 4 to 12 cycles (MRC Myeloma VII); up to 12 cycles (MRC Myeloma V)
====Subsequent treatment====
*MRC Myeloma VII: Interferon alfa-2a maintenance
===References===
# MRC Myeloma V: MacLennan IC, Chapman C, Dunn J, Kelly K; Medical Research Council Working Party for Leukaemia in Adults. Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. Lancet. 1992 Jan 25;339(8787):200-5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# MRC Myeloma VII: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002599
# MRC Myeloma VIII: NCT00002653
==BiRd==
BiRd: Biaxin (Clarithromycin), Revlimid (Lenalidomide), low-dose dexamethasone
C-Rd: Clarithromycin, Revlimid (Lenalidomide), low-dose dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Niesvizky et al. 2007 	2004-2006 	Phase 2 	 	
Puig et al. 2021 (GEM-CLARIDEX)	2015-2019 	Phase 3 (E-esc-ic)	Rd 	Did not meet primary endpoint of PFSMedian PFS: 23 vs 29 mo(HR 1.29), 95% CI 0.92-1.82)
====Chemotherapy====
*Clarithromycin (Biaxin) as follows:
**Cycle 1: 500 mg PO twice per day on days 2 to 28 
**Cycle 2 onwards: 500 mg PO twice per day on days 1 to 28
====Glucocorticoid therapy====
*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
====Targeted therapy====
*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
====Supportive therapy====
*Aspirin 81 mg PO once per day 
*Omeprazole (Prilosec) 20 mg PO once per day 
*Trimethoprim-Sulfamethoxazole (Bactrim DS) PO twice per day, 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00151203
## 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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC
#GEM-CLARIDEX: Puig N, Hernández MT, Rosiñol L, González E, de Arriba F, Oriol A, González-Calle V, Escalante F, de la Rubia J, Gironella M, Ríos R, García-Sánchez R, Arguiñano JM, Alegre A, Martín J, Gutiérrez NC, Calasanz MJ, Martín ML, del Carmen Couto M, Casanova M, Arnao M, Pérez-Persona E, Garzón S, González MS, Martín-Sánchez G, Ocio EM, Coleman M, Encinas C, Vale AM, Teruel AI, Cortés-Rodríguez M, Paiva B, Cedena MT, San-Miguel JF, Lahuerta JJ, Bladé J, Niesvizky R, Mateos MV. Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial. Blood Cancer J. 2021 May 21;11(5):101. link to original article link to PMC article EuroPMC NCT02575144
==mCOP/MP==
mCOP/MP: modified Cyclophosphamide, Oncovin (Vincristine), Prednisolone alternating with Melphalan & Prednisolone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Takenaka et al. 2004 (JCOG 9301)	1993-1998 	Phase 3 (C)	MCNU-COP/MP	Did not meet primary endpoint of OS
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 350 mg/m2 IV once per day on days 1 & 8
*Vincristine (Oncovin) 1 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
*Melphalan (Alkeran) 6 mg/m2 PO once per day on days 22 to 24
====Glucocorticoid therapy====
*Prednisolone (Millipred) 40 mg/m2 PO once per day on days 1 to 3, 8 to 10, 22 to 24
42-day cycles
===References===
# JCOG 9301: Takenaka T, Itoh K, Suzuki T, Utsunomiya A, Matsuda S, Chou T, Sai T, Sano M, Konda S, Ohno T, Mikuni C, Deura K, Yamada T, Mizorogi F, Nagoshi H, Tomonaga M, Hotta T, Kawano K, Tsushita K, Hirano M, Shimoyama M; Lymphoma Study Group of the Japan Clinical Oncology Group. Phase III study of ranimustine, cyclophosphamide, vincristine, melphalan, and prednisolone (MCNU-COP/MP) versus modified COP/MP in multiple myeloma: a Japan clinical oncology group study, JCOG 9301. Int J Hematol. 2004 Feb;79(2):165-73. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==C-VAMP==
C-VAMP: Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), MethylPrednisolone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Raje et al. 1997 	1985-1994 	Non-randomized 	 	
Child et al. 2003 (MRC Myeloma VII)	1993-2000 	Phase 3 (E-switch-ic)	ABCM 	Seems to have longer OS (co-primary endpoint)
Note: A minimum of 3 cycles were given before stem cell harvest.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) by the following renal function-based criteria:
**Serum creatinine 3.4 mg/dL or less: 500 mg IV once per day on days 1, 8, 15
*Vincristine (Oncovin) 0.4 mg IV once per day on days 1 to 4
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 1000 mg/m2 (maximum dose of 1500 mg) IV or PO once per day on days 1 to 5
 
21-day cycles; given until maximal response was achieved
====Subsequent treatment====
*MRC Myeloma VII: Cyclophosphamide & G-CSF stem cell mobilization, then high-dose melphalan & methylprednisolone with auto HSCT consolidation
===References===
# Raje N, Powles R, Kulkarni S, Milan S, Middleton G, Singhal S, Mehta J, Millar B, Viner C, Raymond J, Treleaven J, Cunningham D, Gore M. A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma. Br J Haematol. 1997 Apr;97(1):153-60. link to original article EuroPMC
# MRC Myeloma VII: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002599
==Cyclophosphamide monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Korst et al. 1964	Not reported to 1963	Non-randomized
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 2 mg/kg PO once per day
Continued indefinitely
===References===
# Korst DR, Clifford GO, Fowler WM, Louis J, Will J, Wilson HE. Multiple myeloma II: analysis of cyclophosphamide therapy in 165 patients. JAMA. 1964 Sep 7;189:758-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==CVP==
CVP: Cyclophosphamide, Vincristine, Prednisone
VCP: Vincristine, Cyclophosphamide, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Durie et al. 1986 (SWOG S7927/S7928)	1979-1982 	Phase 3 (C)	VMCP/VBAP 	Seems to have shorter OS
====Chemotherapy====
*Vincristine (Oncovin) 1 mg IV once on day 1
*Cyclophosphamide (Cytoxan) 180 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
21-day cycle for 9 to 26 cycles
===References===
# SWOG S7927/S7928: Durie BG, Dixon DO, Carter S, Stephens R, Rivkin S, Bonnet J, Salmon SE, Dabich L, Files JC, Costanzi JJ. Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1986 Aug;4(8):1227-37. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Dexamethasone monotherapy==
===Regimen variant #1, 35-day cycles===
Study 	Dates of enrollment	Evidence
Alexanian et al. 1986	1983-1985 	Non-randomized
Alexanian et al. 1992	1989-1991 	Non-randomized
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg/m2 PO once per day on days 1 to 4, 9 to 12, 17 to 20
35-day cycle for 3 cycles (Alexanian et al. 1992) or until maximal response (Alexanian et al. 1986)
====Subsequent treatment====
*Alexanian et al. 1992, responders: Interferon alfa maintenance
*Alexanian et al. 1992, non-responders: unclear from manuscript
===Regimen variant #2, indefinite with 35-day induction cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zonder et al. 2010 (SWOG S0232)	2004-2007 	Phase 3 (C)	Len-Dex 	Shorter PFS
Note: This regimen was intended for transplantation-ineligible or -denying patients who had to have symptomatic disease with a measurable M-protein, be at least 18 years old, and have a performance status less than 3 (unless resulting from myeloma). Note that the first 3 cycles, termed "induction" in the protocol, were 35-day cycles. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 3: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
**Cycle 4 onwards: 40 mg PO once per day on days 1 to 4
====Supportive therapy====
*Aspirin 325 mg PO once per day unless already on anticoagulation therapy
35-day cycle for 3 cycles, then 28-day cycles
===Regimen variant #3, indefinite with 28-day induction cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rajkumar et al. 2008 (THAL-MM-003)	2003-2005 	Phase 3 (C)	TD 	Shorter TTPMedian TTP: 6.5 vs 22.6 mo(HR 2.33, 95% CI 1.72-3.12)
Note: This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Glucocorticoid therapy====
*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 variant #4, indefinite with alternating dexamethasone intensity===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Rajkumar et al. 2005 (ECOG E1A00)	2002-06 to 2003-04 	Phase 3 (C)	TD 	Seems to have lower RR within 4 months	Less toxicity
Note: This regimen was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.
====Glucocorticoid therapy====
*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 variant #5, 12 cycles total===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Facon et al. 2005 (IFM 95-01)	1995-1998 	Phase 3 (E-de-esc)	1. DEX-IFN2. MP 3. M-DEX	Did not meet primary endpoint of OS
Note: 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.
====Glucocorticoid therapy====
*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
42-day cycle for 12 cycles
===References===
# Alexanian R, Barlogie B, Dixon D. High-dose glucocorticoid treatment of resistant myeloma. Ann Intern Med. 1986 Jul;105(1):8-11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Alexanian R, Dimopoulos MA, Delasalle K, Barlogie B. Primary dexamethasone treatment of multiple myeloma. Blood. 1992 Aug 15;80(4):887-90. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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. 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 dosing details in abstract have been reviewed by our editors EuroPMC
# ECOG E1A00: Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; ECOG. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006 Jan 20;24(3):431-6. Epub 2005 Dec 19. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00033332
# THAL-MM-003: Rajkumar SV, Rosiñol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, Olesnyckyj M, Yu Z, Knight R, Zeldis JB, Bladé J. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008 May 1;26(13):2171-7. Epub 2008 Mar 24. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00057564
# SWOG S0232: Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B; SWOG. 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 link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00064038
==DEX-IFN==
DEX-IFN: DEXamethasone & InterFeroN alfa-2b
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Facon et al. 2005 (IFM 95-01)	1995-1998 	Phase 3 (E-de-esc)	1. Dexamethasone2. MP 3. M-DEX	Did not meet primary endpoint of OS
Note: 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.
====Glucocorticoid therapy====
*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
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 3,000,000 units SC 3 times per week; start with dexamethasone and stop on on day 42 of the last cycle of dexamethasone
42-day 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. 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 dosing details in abstract have been reviewed by our editors EuroPMC
==DECA==
DECA: Dexamethasone, Etoposide, Cisplatin, Ara-C (Cytarabine)
EDAP: Etoposide, Dexamethasone, Ara-C (Cytarabine), Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence
Barlogie et al. 1997 (Total Therapy 1)	1990-1994 	Non-randomized
Note: This was given as a component of Total Therapy.
====Chemotherapy====
*Etoposide (Vepesid) 100 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose: 400 mg/m2)
*Cytarabine (Ara-C) 1000 mg/m2 IV once on day 5
*Cisplatin (Platinol) 25 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose: 100 mg/m2)
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 5
One course
===References===
# Total Therapy 1: Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. link to original article EuroPMC
## Update: Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
==Lenalidomide & Dexamethasone (RD)==
RD: Revlimid (Lenalidomide) & high-dose Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rajkumar et al. 2009 (ECOG E4A03)	2004-2006 	Phase 3 (C)	Rd 	Shorter OS
Note: This is the high-dose dexamethasone arm, and was intended for patients with previously untreated symptomatic multiple myeloma, bone marrow plasmacytosis (greater than or equal to 10% plasma cells or sheets of plasma cells) or a biopsy-proven plasmacytoma, and measurable disease defined as serum monoclonal protein more than 1 g/dL and/or urine monoclonal protein greater than or equal to 200 mg/24 h.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
====Supportive therapy====
*One of the following bisphosphonates:
**Pamidronate (Aredia) 90 mg IV over 2 to 4 hours once on day 1
**Zoledronic acid (Zometa) 4 mg IV over 15 minutes once on day 1
*Thromboprophylaxis mandatory (added mid-protocol after excess rates of DVT)
28-day cycle for 4 cycles (see below)
====Subsequent treatment====
*ECOG E4A03, responding patients could choose after 4 cycles to proceed to: high-dose melphalan with autologous hematopoietic stem cell transplant consolidation or to continue RD until progression of disease or intolerable toxicity
*ECOG E4A03, non-responders were transitioned to: Second-line Thal-Dex (details not described)
===References===
# ECOG E4A03: Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; ECOG. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21. Erratum in: Lancet Oncol. 2010 Jan;11(1):14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00098475
## Subgroup analysis: Jacobus SJ, Kumar S, Uno H, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, Williams ME, Siegel DS, Greipp PR, Rajkumar SV, Fonseca R. Impact of high-risk classification by FISH: an eastern cooperative oncology group (ECOG) study E4A03. Br J Haematol. 2011 Nov;155(3):340-8. Epub 2011 Sep 9. link to original article link to PMC article EuroPMC
==Melphalan monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bergsagel et al. 1965 	Not reported 	Non-randomized 	 	
Hoogstraten et al. 1967 	Not reported 	Non-randomized part of RCT	 	
Rivers & Patno 1969 	1960-1962 	Phase 3 (E-switch-ic) 	Cyclophosphamide	Did not meet endpoint of OS
Hoogstraten et al. 1969a 	Not reported 	Non-randomized 	 	
MacLennan et al. 1992 (MRC Myeloma V)	1982-1986 	Phase 3 (C) 	ABCM 	Shorter OS
====Chemotherapy====
*Melphalan (Alkeran) 7 mg/m2 PO once per day on days 1 to 4
21-day cycles
===References===
# Bergsagel DE, Migliore PJ, Griffith KM. Myeloma proteins and the clinical response to melphalan therapy. Science. 1965 Apr 16;148(3668):376-7. link to original article EuroPMC
# Hoogstraten B, Sheehe PR, Cuttner J, Cooper T, Kyle RA, Oberfield RA, Townsend SR, Harley JB, Hayes DM, Costa G, Holland JF. Melphalan in multiple myeloma. Blood. 1967 Jul;30(1):74-83. link to original article EuroPMC
# Rivers SL, Patno ME. Cyclophosphamide vs melphalan in treatment of plasma cell myeloma. JAMA. 1969 Feb 17;207(7):1328-34. link to original article EuroPMC
# Hoogstraten B, Costa J, Cuttner J, Forcier J, Leone LA, Harley JB, Glidewell OJ. Intermittent melphalan therapy in multiple myeloma. JAMA. 1969 Jul 14;209(2):251-3. link to original article EuroPMC
# MRC Myeloma V: MacLennan IC, Chapman C, Dunn J, Kelly K; Medical Research Council Working Party for Leukaemia in Adults. Combined chemotherapy with ABCM versus melphalan for treatment of myelomatosis. Lancet. 1992 Jan 25;339(8787):200-5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Melphalan & Dexamethasone==
M-DEX: Melphalan & DEXamethasone
MD: Melphalan & Dexamethasone
===Regimen variant #1, 0.25/40===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Facon et al. 2005 (IFM 95-01)	1995-1998 	Phase 3 (E-esc-ic)	1. Dexamethasone2. MP3. DEX-IFN	Did not meet primary endpoint of OS
Note: 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
====Glucocorticoid therapy====
*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
42-day cycle for 12 cycles
===Regimen variant #2, 9/20===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Hernández et al. 2004 (MM-PETHEMA 96)	1997 to not reported	Phase 3 (E-switch-ic)	MP 	Did not meet endpoints of ORR/OS
Note: This was an experimental arm that did not meet its endpoints; included here because other variants of this regimen have demonstrated comparative superiority.
====Chemotherapy====
*Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 9 to 12
28-day cycles
===References===
# MM-PETHEMA 96: Hernández JM, García-Sanz R, Golvano E, Bladé J, Fernandez-Calvo J, Trujillo J, Soler JA, Gardella S, Carbonell F, Mateo G, San Miguel JF. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br J Haematol. 2004 Oct;127(2):159-64. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# IFM 95-01: 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. 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Melphalan & Prednisone (MP)==
MP: Melphalan & Prednisone
===Regimen variant #1, melphalan 0.15 mg/kg===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hansen et al. 1985	1979-1983 	Phase 3 (C)	1. VMP (Vincristine)2. VBCMP	Did not meet primary endpoint of RFS
====Chemotherapy====
*Melphalan (Alkeran) 0.15 mg/kg PO once per day on days 1 to 7
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycle 1: 0.6 mg/kg PO once per day on days 1 to 14
**Cycle 2 onwards: 0.3 mg/kg PO once per day on days 1 to 7
28-day cycles
===Regimen variant #2, melphalan 0.18 mg/kg===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Palumbo et al. 2012 (MM-015)	2007-02 to 2008-09 	Phase 3 (C)	1. MPR 	Did not meet primary endpoint of PFS
Palumbo et al. 2012 (MM-015)	2007-02 to 2008-09 	Phase 3 (C)	2. MPR-R 	Shorter PFS
Note: This regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (greater than or equal to 65 years of age).
====Chemotherapy====
*Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4 
====Supportive therapy====
*Thromboprophylaxis: Aspirin 75 to 100 mg PO once per day
28-day cycle for 9 cycles
===Regimen variant #3, melphalan 0.2 mg/kg===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hulin et al. 2009 (IFM 01/01)	2002-2006 	Phase 3 (C)	MPT 	Seems to have shorter OSMedian OS: 29.1 vs 44 mo(HR 1.47, 95% CI 1.04-2.08)
Note: 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
====Glucocorticoid therapy====
*Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
42-day cycle for 12 cycles
===Regimen variant #4, melphalan 0.25 mg/kg x 4 d/cycle, prednisone 2 mg/kg===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Alexanian et al. 1969 (SWG01)	1965-1968 	Non-randomized (RT)	 	
Alexanian et al. 1972 	1968-1971 	Phase 3 (C) 	MPP 	Did not meet endpoints of DOR/OS
Facon et al. 2005 (IFM 95-01)	1995-1998 	Phase 3 (C) 	1. Dexamethasone2. M-DEX 3. DEX-IFN	Did not meet primary endpoint of OS
Facon et al. 2007 (IFM 99-06)	2000-2005 	Phase 3 (C) 	1. MPT 	Shorter OS
Facon et al. 2007 (IFM 99-06)	2000-2005 	Phase 3 (C) 	2. VAD, then MEL100 	Did not meet primary endpoint of OS
Note: 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. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Chemotherapy====
*Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
42-day cycle for 12 cycles (IFM 95-01 & IFM 99-06) or indefinitely (Alexanian et al. 1972 & SWG01)
===Regimen variant #5, melphalan 0.25 mg/kg x 4 d/cycle, flat dose prednisone===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hjorth et al. 1996 	1990-1992 	Phase 3 (C)	MP & IFN alfa-2b	Did not meet primary endpoint of OS
Waage et al. 2010 (NMSG12)	2002-2007 	Phase 3 (C)	MPT 	Did not meet primary endpoint of OS
Note: In NMSG12, this regimen was intended for patients with previously untreated symptomatic MM, who were not eligible for high-dose treatment with autologous stem cell support.
====Chemotherapy====
*Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
42-day cycles
Treatment was continued until plateau phase.
===Regimen variant #6, melphalan 0.25 mg/kg x 5 d/cycle===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Wijermans et al. 2010 (HOVON 49)	2002-2007 	Phase 3 (C)	MP-T 	Might have shorter OS
Note: 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
====Glucocorticoid therapy====
*Prednisone (Sterapred) 1 mg/kg PO once per day on days 1 to 5 
====Supportive therapy====
*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 variant #7, melphalan 4 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Palumbo et al. 2006 (GISMM2001-A)	2002-2005 	Phase 3 (C)	MPT 	Seems to have shorter PFS
Note: 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
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 7 
28-day cycle for 6 cycles
===Regimen variant #8, melphalan 9 mg/m2 x 8===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
San Miguel et al. 2008 (VISTA)	2004-2006 	Phase 3 (C)	VMP 	Shorter OS
Note: This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions.
====Chemotherapy====
*Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
42-day cycle for 8 cycles
===Regimen variant #9, melphalan 9 mg/m2 x 9===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Beksac et al. 2010 (TMSG-2005-001)	2006-2009 	Phase 3 (C)	MPT 	Seems to have lower ORR
Note: This regimen was intended for patients with newly diagnosed, untreated, symptomatic, measurable myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting conditions.
====Chemotherapy====
*Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
42-day cycle for 9 cycles
===Regimen variant #10, melphalan 9 mg/m2 x 12===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Shustik et al. 2007 (NCIC-CTG MY.7)	1995-2003 	Phase 3 (C)	MD 	Did not meet primary endpoint of PFS
====Chemotherapy====
*Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
28-day cycle for 12 cycles
====Subsequent treatment====
*Dexamethasone maintenance versus no further treatment
===Regimen variant #11, melphalan 9 mg/m2, indefinite===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bergsagel et al. 1979 	1973-1977 	Phase 3 (C)	1. B/C/M2. BCM	Did not meet primary endpoint of OS
Hernández et al. 2004 (MM-PETHEMA 96)	1997 to not reported	Phase 3 (C)	MD 	Did not meet endpoints of ORR/OS
====Chemotherapy====
*Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) by the following study-specific criteria:
**Bergsagel et al. 1979: 100 mg PO once per day on days 1 to 4
**MM-PETHEMA 96: 60 mg/m2 PO once per day on days 1 to 4
28-day cycles
===Regimen variant #12, melphalan 15 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Pönisch et al. 2006	1994-1999 	Phase 3 (C)	BP 	Shorter TTF
====Chemotherapy====
*Melphalan (Alkeran) 15 mg/m2 IV over 30 minutes once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg IV or PO once per day on days 1 to 4 
28-day cycles
===Regimen variant #13, melphalan 16 mg/m2 and tapering prednisone===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cooper et al. 1986 (CALGB 7761)	1977-09 to 1982-02 	Phase 3 (E-de-esc)	1. MCBP2. Seq-MCBP3. MCBPA	No difference in response rates
====Chemotherapy====
*Melphalan (Alkeran) as follows:
**Cycle 1: 16 mg/m2 IV once per day on days 1, 15, 29
**Cycles 2 to 18: 16 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycle 1: 0.8 mg/kg (route not specified) once per day on days 1 to 14, then 0.4 mg/kg (route not specified) once per day on days 15 to 28, then 0.2 mg/kg (route not specified) once per day on days 29 to 42 
42-day course, then 28-day cycle for up to 17 cycles
===References===
# SWG01: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# Alexanian R, Bonnet J, Gehan E, Haut A, Hewlett J, Lane M, Monto R, Wilson H. Combination chemotherapy for multiple myeloma. Cancer. 1972 Aug;30(2):382-9. link to original article EuroPMC
# Bergsagel DE, Bailey AJ, Langley GR, MacDonald RN, White DF, Miller AB. The chemotherapy on plasma-cell myeloma and the incidence of acute leukemia. N Engl J Med. 1979 Oct 4;301(14):743-8. link to original article EuroPMC
# Hansen OP, Clausen NA, Drivsholm A, Laursen B. Phase III study of intermittent 5-drug regimen (VBCMP) versus intermittent 3-drug regimen (VMP) versus intermittent melphalan and prednisone (MP) in myelomatosis. Scand J Haematol. 1985 Nov;35(5):518-24. link to original article EuroPMC
#CALGB 7761: Cooper MR, McIntyre OR, Propert KJ, Kochwa S, Anderson K, Coleman M, Kyle RA, Prager D, Rafla S, Zimmer B. Single, sequential, and multiple alkylating agent therapy for multiple myeloma: a CALGB Study. J Clin Oncol. 1986 Sep;4(9):1331-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Hjorth M, Westin J, Dahl IMS, Gimsing P, Hippe E, Holmberg E, Lamvik J, Lanng Nielsen J, Lofvenberg E, Palva IP, Rodjer S, Talstad I, Turesson I, Wisloff F, Zador G; Nordic Myeloma Study Group. Interferon-alpha 2b added to melphalan-prednisone for initial and maintenance therapy in multiple myeloma: a randomized, controlled trial. Ann Intern Med. 1996 Jan 15;124(2):212-22. link to original article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# MM-PETHEMA 96: Hernández JM, García-Sanz R, Golvano E, Bladé J, Fernandez-Calvo J, Trujillo J, Soler JA, Gardella S, Carbonell F, Mateo G, San Miguel JF. Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma. Br J Haematol. 2004 Oct;127(2):159-64. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# IFM 95-01: 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. 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# GISMM2001-A: Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00232934
## 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 dosing details in abstract have been reviewed by our editors EuroPMC
# Pönisch W, Mitrou PS, Merkle K, Herold M, Assmann M, Wilhelm G, Dachselt K, Richter P, Schirmer V, Schulze A, Subert R, Harksel B, Grobe N, Stelzer E, Schulze M, Bittrich A, Freund M, Pasold R, Friedrich T, Helbig W, Niederwieser D; East German Study Group of Hematology and Oncology. Treatment of bendamustine and prednisone in patients with newly diagnosed multiple myeloma results in superior complete response rate, prolonged time to treatment failure and improved quality of life compared to treatment with melphalan and prednisone--a randomized phase III study of the East German Study Group of Hematology and Oncology (OSHO). J Cancer Res Clin Oncol. 2006 Apr;132(4):205-12. Epub 2006 Jan 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# NCIC-CTG MY.7: Shustik C, Belch A, Robinson S, Rubin SH, Dolan SP, Kovacs MJ, Grewal KS, Walde D, Barr R, Wilson J, Gill K, Vickars L, Rudinskas L, Sicheri DA, Wilson K, Djurfeldt M, Shepherd LE, Ding K, Meyer RM. A randomised comparison of melphalan with prednisone or dexamethasone as induction therapy and dexamethasone or observation as maintenance therapy in multiple myeloma: NCIC CTG MY.7. Br J Haematol. 2007 Jan;136(2):203-11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002678
# IFM 99-06: Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H; Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18. link to original article dosing details in abstract have been reviewed by our editors EuroPMC content property of HemOnc.org NCT00367185
# VISTA: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00111319
## 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 dosing details in abstract have been reviewed by our editors EuroPMC
##HRQoL analysis: Delforge M, Dhawan R, Robinson D Jr, Meunier J, Regnault A, Esseltine DL, Cakana A, van de Velde H, Richardson PG, San Miguel JF. Health-related quality of life in elderly, newly diagnosed multiple myeloma patients treated with VMP vs MP: results from the VISTA trial. Eur J Haematol. 2012 Jul;89(1):16-27. Epub 2012 May 7. link to original article EuroPMC
## 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 EuroPMC 
# IFM 01/01: Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, Dib M, Guillerm G, Salles B, Eschard JP, Lenain P, Casassus P, Azaïs I, Decaux O, Garderet L, Mathiot C, Fontan J, Lafon I, Virion JM, Moreau P. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009 Aug 1;27(22):3664-70. Epub 2009 May 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00644306
# NMSG12: Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00218855
# HOVON 49: Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; 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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN90692740
# TMSG-2005-001: Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00934154
# 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; HOVON; 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 EuroPMC
# MM-015: Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00405756
==MP (Prednisolone)==
MP: Melphalan & Prednisolone
===Regimen variant #1, melphalan 0.25 mg/kg===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Keldsen et al. 1993	1987-1989 	Phase 3 (C)	NOP 	Seems to have longer OS
====Chemotherapy====
*Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 to 200 mg PO once per day on days 1 to 4
28-day cycle for 13 cycles (1 year)
===Regimen variant #2, melphalan 7 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX)	2003-2007 	Phase 3 (C)	CTDa 	Not reported
Note: This was a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference.
====Chemotherapy====
*Melphalan (Alkeran) 7 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisolone (Millipred) 40 mg PO once per day on days 1 to 4 
====Supportive therapy====
*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
====Subsequent treatment====
*Thalidomide maintenance versus no further treatment
===References===
# Keldsen N, Bjerrum OW, Dahl IM, Drivsholm A, Ellegaard J, Gadeberg O, Gimsing P, Grønvold T, Hansen MM, Hippe E, Lamvik J, Ly B, Skarbøvik A, Talstad I, Thorling K, Wesenberg K, Wisløff F; Nordic Myeloma Study Group. Multiple myeloma treated with mitoxantrone in combination with vincristine and prednisolone (NOP regimen) versus melphalan and prednisolone: a phase III study. Eur J Haematol. 1993 Aug;51(2):80-5. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article EuroPMC ISRCTN68454111
## Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## 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 EuroPMC
#RHG-MM97: NCT00003603
==VAD==
VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
VAd: Vincristine, Adriamycin (Doxorubicin), low-dose dexamethasone
===Regimen variant #1, 0.4/9/40 x 3 (bolus doxorubicin & vincristine, dex 12 days/cycle)===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Sonneveld et al. 2012 (HOVON-65)	2005-2008 	Phase 3 (C)	PAD 	Shorter PFS1
Sonneveld et al. 2012 (GMMG-HD4)	2005-2008 	Phase 3 (C)	PAD 	Shorter PFS1
1Observed efficacy is for induction PAD, then transplant, then maintenance bortezomib compared with induction VAD, then transplant, then maintenance thalidomide.
Note: 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. Stem cells collected 4 to 6 weeks after induction therapy. HOVON-65/GMMG-HD4 was a single phase 3 RCT but the consolidation was different by group, so is reported here as 2 distinct trials.
====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
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
====Supportive therapy====
*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/day PO (did not specify whether taken once per day or as a divided twice per day dose)
**Valacyclovir (Valtrex) 1000 mg/day PO (did not specify whether taken once per day or as a divided twice per day dose)
28-day cycle for 3 cycles
====Subsequent treatment====
*HOVON-65: Single autologous hematopoietic cell transplant consolidation
*GMMG-HD4: Tandem autologous hematopoietic cell transplant consolidation
===Regimen variant #2, 0.4/9/40 x 4 (CI doxorubicin, bolus vincristine, dex 12 days/cycle in cycles 1 & 2)===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Harousseau et al. 2010 (IFM 2005-01)	2005-2008 	Phase 3 (C)	VD 	Might have shorter PFS
Note: This regimen was intended for patients age less than or equal to 65 years with untreated symptomatic MM with measurable paraprotein in serum (greater than 1.0 g/dL) or urine (greater than 0.2 g/24 h).
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg) 
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
====Glucocorticoid therapy====
*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 day on days 1 to 4
====Supportive therapy====
*One of the following, until first transplant:
**Pamidronate (Aredia) 90 mg IV once on day 1
**Zoledronic acid (Zometa) 4 mg IV once on day 1
*"Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."
28-day cycle for 4 cycles
====Subsequent treatment====
*DCEP versus high-dose melphalan with autologous hematopoietic cell transplant consolidation
===Regimen variant #3, 0.4/9/40 (CI doxorubicin & vincristine, dex 4 days/cycle)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cook et al. 2004 (WOS MM1) 	1996-2002 	Phase 3 (C) 	Z-Dex 	Might have higher ORR
Attal et al. 2006 (IFM 99-02)	2000-2003 	Non-randomized part of phase 3 RCT	 	
Rifkin et al. 2006 (CR002434)	2001-2003 	Phase 3 (C) 	DVd 	Non-inferior ORR
Straka et al. 2016 (DSMM-II) 	2001-2006 	Phase 3 (C) 	No induction	Did not meet primary endpoint of PFS
Note: This regimen was intended for patients greater than or equal to 18 years and fulfilling a diagnosis of stage II or III MM according to the Durie and Salmon criteria. Note that Straka et al. 2016 does not describe dosing; placed here given that it is contemporary to these trials.
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg) 
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2) 
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles
====Subsequent treatment====
*IFM 99-02: MEL140 & MEL200 tandem auto HSCT consolidation, after 3 to 4 cycles
===Regimen variant #4, 0.4/9/40 (CI doxorubicin & vincristine, dex 8 days/cycle)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Friedenberg et al. 2006 (ECOG E1A95)	1997-2000 	Phase 3 (C)	VAD & Valspodar	Might have longer OS
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg) 
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2) 
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 15 to 18
28-day cycles
===Regimen variant #5, 0.4/9/40 (bolus doxorubicin & vincristine, dex 12 days/cycle in cycles 1-3)===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Dimopoulos et al. 2003	1999-2001 	Phase 3 (C)	VAD doxil 	Did not meet primary endpoint of ORR
Note: 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
====Glucocorticoid therapy====
*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 therapy====
*Fluconazole (Diflucan) 200 mg PO once per day 
*Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO twice per day for "prophylaxis"
28-day cycle for 4 cycles
===Regimen variant #6, 0.4/9/40 (CI doxorubicin & vincristine, dex 12 days/cycle)===
Study 	Dates of enrollment 	Evidence
Barlogie et al. 2006 (SWOG S9321)	1993 to not reported	Non-randomized part of phase 3 RCT
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
====Supportive therapy====
*Cimetidine (Tagamet) prophylaxis (dose not specified)
*Trimethoprim/Sulfamethoxazole prophylaxis (dose not specified)
35-day cycle for 4 cycles
====Subsequent treatment====
*SWOG S9321, SD or better: VBMCP versus melphalan & TBI, then auto HSCT consolidation
===Regimen variant #7, 0.4/9/40 (Bolus doxorubicin, CI vincristine, dex 12 days per odd cycle)===
Study 	Dates of enrollment	Evidence
Segeren et al. 1999	1995-1998 	Phase 2
====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
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Odd cycles: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
====Supportive therapy====
*Fluconazole (Diflucan) 200 mg PO once per day 
*Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO twice per day for "prophylaxis"
28-day cycles
===Regimen variant #8, 0.4/9/40 (CI doxorubicin & vincristine, dex 4 days per odd cycle)===
Study 	Dates of enrollment	Evidence
Samson et al. 1989 	1984-1988 	Non-randomized
Cavo et al. 2007 (Bologna 96)	1996-2001 	Non-randomized part of phase 3 RCT
Note: In Samson et al. 1989, the odd cycles were 21 days in length. In Bologna 96, 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 96 hours, started on day 1 (total dose per cycle: 1.6 mg) 
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
====Glucocorticoid therapy====
*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 (Bologna 96) or indefinitely (Samson et al. 1989)
====Subsequent treatment====
*Bologna 96, responders: Single autologous hematopoietic cell transplant versus tandem autologous hematopoietic cell transplant consolidation
===Regimen variant #9, 2/50/40===
Study 	Dates of enrollment	Evidence
Corso et al. 2004	1996-2002 	Phase 2
====Chemotherapy====
*Vincristine (Oncovin) 2 mg IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV once per day on days 1 to 4, 14 to 17
2 cycles (length not specified)
====Subsequent treatment====
*DCEP & G-CSF stem cell mobilization, then high dose melphalan with auto HSCT consolidation
===References===
# Samson D, Gaminara E, Newland A, Van de Pette J, Kearney J, McCarthy D, Joyner M, Aston L, Mitchell T, Hamon M, Barrett AJ, Evans M. Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet. 1989 Oct 14;2(8668):882-5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# WOS MM1: Cook G, Clark RE, Morris TC, Robertson M, Lucie NP, Anderson S, Paul J, Franklin IM. A randomized study (WOS MM1) comparing the oral regime Z-Dex (idarubicin and dexamethasone) with vincristine, adriamycin and dexamethasone as induction therapy for newly diagnosed patients with multiple myeloma. Br J Haematol. 2004 Sep;126(6):792-8. link to original article EuroPMC NCT00006232
# IFM99-03: 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 EuroPMC
## Pooled 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. 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 EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# ECOG E1A95: Friedenberg WR, Rue M, Blood EA, Dalton WS, Shustik C, Larson RA, Sonneveld P, Greipp PR. Phase III study of PSC-833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95): a trial of the Eastern Cooperative Oncology Group. Cancer. 2006 Feb 15;106(4):830-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002878
# CR002434: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00344422
# IFM 99-02: Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker L, Yakoub Agha I, Bourhis JH, Garderet L, Pegourie B, Dumontet C, Renaud M, Voillat L, Berthou C, Marit G, Monconduit M, Caillot D, Grobois B, Avet-Loiseau H, Moreau P, Facon T; 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00222053
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# Bologna 96: Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00378222
## Subgroup 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 dosing details in abstract have been reviewed by our editors EuroPMC
# SWOG S9321: 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 EuroPMC NCT00002548
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# HOVON-50: Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00028886
## Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article EuroPMC
# IFM 2005-01: Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00200681
# HOVON-65: 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 dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN64455289
## 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 EuroPMC
## Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article EuroPMC
# GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN64455289
## 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 EuroPMC
## Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article EuroPMC
# DSMM-II: Straka C, Liebisch P, Salwender H, Hennemann B, Metzner B, Knop S, Adler-Reichel S, Gerecke C, Wandt H, Bentz M, Bruemmendorf TH, Hentrich M, Pfreundschuh M, Wolf HH, Sezer O, Bargou R, Jung W, Trümper L, Hertenstein B, Heidemann E, Bernhard H, Lang N, Frickhofen N, Hebart H, Schmidmaier R, Sandermann A, Dechow T, Reichle A, Schnabel B, Schäfer-Eckart K, Langer C, Gramatzki M, Hinke A, Emmerich B, Einsele H. Autotransplant with and without induction chemotherapy in older multiple myeloma patients: long-term outcome of a randomized trial. Haematologica. 2016 Nov;101(11):1398-1406. Epub 2016 Aug 4. link to original article link to PMC article does not contain dosing details EuroPMC NCT02288741
==VAMP==
VAMP: Vincristine, Adriamycin (Doxorubicin), MethylPrednisolone
===Regimen variant #1, lower-dose steroid===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Fermand et al. 1998	1990-1995 	Phase 3 (E-switch-ic)	VMCP 	Seems to have longer EFS
Fermand et al. 2005	1991-1998 	Phase 3 (E-switch-ic)	VMCP 	Might have longer EFS
Note: this is to be distinguished from the VAMP protocols used in AML and Hodgkin lymphoma.
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion of 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion of 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 400 mg IV once per day on days 1 to 4
1-month cycle for 3 to 4 cycles
====Subsequent treatment====
*Fermand et al. 1998: Lomustine, melphalan, TBI with auto HSCT consolidation
*Fermand et al. 2005: MEL200 with auto HSCT or melphalan & busulfan with auto HSCT consolidation
===Regimen variant #2, higher-dose steroid===
Study 	Dates of enrollment	Evidence
Gore et al. 1989	1985-1988 	Phase 2
Note: this is to be distinguished from the VAMP protocols used in AML and Hodgkin lymphoma.
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion of 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion of 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 1500 mg IV or PO once per day on days 1 to 5
21-day cycles
===Regimen variant #3, with steroid taper===
Study 	Dates of enrollment	Evidence
Raje et al. 1997	1985-1994 	Non-randomized
Note: this is to be distinguished from the VAMP protocols used in AML and Hodgkin lymphoma.
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion of 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion of 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 1500 mg IV or PO once per day on days 1 to 4, then 1000 mg IV or PO once on day 5, then 500 mg IV or PO once on day 6
21-day cycles until maximum response plus 1 cycle
====Subsequent treatment====
*HDM with auto HSCT consolidation
===References===
# Gore ME, Selby PJ, Viner C, Clark PI, Meldrum M, Millar B, Bell J, Maitland JA, Milan S, Judson IR, Tillyer C, Malpas JS, McElwain TJ. Intensive treatment of multiple myeloma and criteria for complete remission. Lancet. 1989 Oct 14;2(8668):879-82. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Raje N, Powles R, Kulkarni S, Milan S, Middleton G, Singhal S, Mehta J, Millar B, Viner C, Raymond J, Treleaven J, Cunningham D, Gore M. A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma. Br J Haematol. 1997 Apr;97(1):153-60. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Fermand JP, Ravaud P, Chevret S, Divine M, Leblond V, Belanger C, Macro M, Pertuiset E, Dreyfus F, Mariette X, Boccacio C, Brouet JC. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998 Nov 1;92(9):3131-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, Arnulf B, Royer B, Mariette X, Pertuiset E, Belanger C, Janvier M, Chevret S, Brouet JC, Ravaud P; Group Myelome-Autogreffe. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005 Dec 20;23(36):9227-33. Epub 2005 Nov 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==VBMCP==
VBMCP: Vincristine, BiCNU (Carmustine), Melphalan, Cyclophosphamide, Prednisone
VBCMP: Vincristine, BiCNU (Carmustine), Cyclophosphamide, Melphalan, Prednisone
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Oken et al. 1997 (ECOG E2479) 	1979-1983 	Phase 3 (E-esc-ic) 	MP 	Higher ORR
Oken et al. 1999 (ECOG E9486) 	1988-1992 	Phase 3 (C) 	1. VBMCP/HiCy 	Did not meet primary endpoint of OS
Oken et al. 1999 (ECOG E9486) 	1988-1992 	Phase 3 (C) 	2. VBMCP/IFN 	Seems to have shorter TTP
Barlogie et al. 2006 (SWOG S9321)	1993 to not reported	Phase 3 (C) 	Melphalan & TBI, then auto HSCT	Did not meet co-primary endpoints of ORR/OS
Kyle et al. 2009 (ECOG E5A93) 	1994-2002 	Non-randomized part of phase 3 RCT	 	
====Chemotherapy====
*Vincristine (Oncovin) 1.2 mg/m2 (maximum dose of 2 mg) IV once on day 1
*Carmustine (BCNU) 20 mg/m2 IV once on day 1
*Melphalan (Alkeran) 8 mg/m2 PO once per day on days 1 to 4
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 7
35-day cycle for 2 cycles
====Subsequent treatment====
*ECOG E5A93: VBMCP/IFN versus VBMCP/HiCy & IFN consolidation
===References===
# Hansen OP, Clausen NA, Drivsholm A, Laursen B. Phase III study of intermittent 5-drug regimen (VBCMP) versus intermittent 3-drug regimen (VMP) versus intermittent melphalan and prednisone (MP) in myelomatosis. Scand J Haematol. 1985 Nov;35(5):518-24. link to original article EuroPMC
# ECOG E2479: Oken MM, Harrington DP, Abramson N, Kyle RA, Knospe W, Glick JH. Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: results of Eastern Cooperative Oncology Group Study E2479. Cancer. 1997 Apr 15;79(8):1561-7. link to original article EuroPMC
# ECOG E9486: Oken MM, Leong T, Lenhard RE Jr, Greipp PR, Kay NE, Van Ness B, Keimowitz RM, Kyle RA. The addition of interferon or high dose cyclophosphamide to standard chemotherapy in the treatment of patients with multiple myeloma: phase III Eastern Cooperative Oncology Group Clinical Trial EST 9486. Cancer. 1999 Sep 15;86(6):957-68. link to original article EuroPMC
# SWOG S9321: 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 EuroPMC NCT00002548
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# ECOG E5A93: Kyle RA, Jacobus S, Friedenberg WR, Slabber CF, Rajkumar SV, Greipp PR. The treatment of multiple myeloma using vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with high-dose cyclophosphamide and alpha(2)beta interferon versus VBMCP: results of a phase III Eastern Cooperative Oncology Group Study E5A93. Cancer. 2009 May 15;115(10):2155-64. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002556
==VBMCP/VBAD==
VBMCP/VBAD: Vincristine, BiCNU (Carmustine), Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, BiCNU (Carmustine), Adriamycin (Doxorubicin), Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence
Bladé et al. 2005 	1994-1999 	Non-randomized part of phase 3 RCT
Rosiñol et al. 2008 (PETHEMA MM 2000)	1999-2004 	Non-randomized part of phase 3 RCT
Note: Dosing instructions for cyclophosphamide were not provided in Bladé et al. 2005.
====Chemotherapy, VBMCP portion (cycles 1 & 3)====
*Vincristine (Oncovin) 0.03 mg/kg (maximum dose of 2 mg) IV once on day 1
*Carmustine (BCNU) 0.5 mg/kg IV once on day 1
*Melphalan (Alkeran) 0.25 mg/kg PO once per day on days 1 to 4
*Cyclophosphamide (Cytoxan) (not specified)
====Glucocorticoid therapy, VBMCP portion (cycles 1 & 3)====
*Prednisone (Sterapred) 1 mg/kg PO once per day on days 1 to 4, then 0.5 mg/kg PO once per day on days 5 to 8, then 0.25 mg/kg PO once per day on days 9 to 12
====Chemotherapy, VBAD portion (cycles 2 & 4)====
*Vincristine (Oncovin) 1 mg IV once on day 1
*Carmustine (BCNU) 30 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
====Glucocorticoid therapy, VBAD portion (cycles 2 & 4)====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
35-day cycle for 4 cycles (see note) 
====Subsequent treatment====
*Bladé et al. 2005, with response after 4 cycles: VBMCP/VBAD continuation x 8 (12 cycles total) versus MEL200 with auto HSCT or MEL140 & TBI with auto HSCT consolidation
*PETHEMA MM 2000: Bu/Mel with tandem auto HSCT versus Bu/Mel with auto HSCT followed by RIC allo HSCT
===References===
# Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; PETHEMA. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. link to original article contains partial dosing details in manuscript EuroPMC
# PETHEMA MM 2000: Rosiñol L, Pérez-Simón JA, Sureda A, de la Rubia J, de Arriba F, Lahuerta JJ, González JD, Díaz-Mediavilla J, Hernández B, García-Frade J, Carrera D, León A, Hernández M, Abellán PF, Bergua JM, San Miguel J, Bladé J; PETHEMA; GEM. A prospective PETHEMA study of tandem autologous transplantation versus autograft followed by reduced-intensity conditioning allogeneic transplantation in newly diagnosed multiple myeloma. Blood. 2008 Nov 1;112(9):3591-3. Epub 2008 Jul 8. link to original article does not contain dosing details EuroPMC NCT00560053
==VMCP==
VMCP: Vincristine, Melphalan, Cyclophosphamide, Prednisone
VCMP: Vincristine, Cyclophosphamide, Melphalan, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Alexanian et al. 1977 (SWOG S7305)	1973-01 to 1974-12 	Phase 3 (E-esc-ic)	Alkylator-prednisone combinations	Longer OS
Fermand et al. 2005 	1991-1998 	Phase 3 (C) 	VAMP, then auto HSCT 	Might have shorter EFS
====Chemotherapy====
*Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
*Melphalan (Alkeran) 6 mg/m2 PO once per day on days 1 to 4
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 80 mg/m2 PO once per day on days 1 to 4
1-month cycles
===References===
# SWOG S7305: Alexanian R, Salmon S, Bonnet J, Gehan E, Haut A, Weick J. Combination therapy for multiple myeloma. Cancer. 1977 Dec;40(6):2765-71. link to original article EuroPMC
# Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, Arnulf B, Royer B, Mariette X, Pertuiset E, Belanger C, Janvier M, Chevret S, Brouet JC, Ravaud P; Group Myelome-Autogreffe. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005 Dec 20;23(36):9227-33. Epub 2005 Nov 7. link to original articledosing details in manuscript have been reviewed by our editors EuroPMC
==VMCP/VBAP==
VMCP/VBAP: Vincristine, Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, BiCNU (Carmustine), Adriamycin (Doxorubicin), Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Durie et al. 1986 (SWOG S7927/S7928) 	1979-1982 	Phase 3 (E-esc-ic) 	VCP 	Seems to have longer OS
Salmon et al. 1990 (SWOG S8229/S8230)	1982-1987 	Non-randomized part of phase 3 RCT	 	
Attal et al. 1996 (IFM90) 	1990-1993 	Non-randomized part of phase 3 RCT	 	
====Chemotherapy, VMCP portion (cycles 1, 3, +/- 5)====
*Vincristine (Oncovin) 1 mg IV once on day 1
*Melphalan (Alkeran) 5 mg/m2 PO once per day on days 1 to 4
*Cyclophosphamide (Cytoxan) 110 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy, VMCP portion (cycles 1, 3, +/- 5)====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
====Chemotherapy, VBAP portion (cycles 2, 4, +/- 6)====
*Vincristine (Oncovin) 1 mg IV once on day 1
*Carmustine (BCNU) 30 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
====Glucocorticoid therapy, VBAP portion (cycles 2, 4, +/- 6)====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
21-day cycle for 4 to 6 cycles
====Subsequent treatment====
*IFM90, patients with a WHO performance status less than 3, creatinine less than 1.7 mg/dL (150 µmol/L), and bone marrow (collected after cycle 4) with greater than 200 million nucleated cells/kg: melphalan, total body irradiation (TBI), and autologous transplant consolidation versus VMCP/VBAP continuation x 18 total cycles
===References===
# SWOG S7927/S7928: Durie BG, Dixon DO, Carter S, Stephens R, Rivkin S, Bonnet J, Salmon SE, Dabich L, Files JC, Costanzi JJ. Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1986 Aug;4(8):1227-37. link to original article EuroPMC
# SWOG S8229/S8230: Salmon SE, Tesh D, Crowley J, Saeed S, Finley P, Milder MS, Hutchins LF, Coltman CA Jr, Bonnet JD, Cheson B, Knost JA, Samhouri A, Beckord J, Stock-Novack D. Chemotherapy is superior to sequential hemibody irradiation for remission consolidation in multiple myeloma: a Southwest Oncology Group study. J Clin Oncol. 1990 Sep;8(9):1575-84. link to original article EuroPMC
# IFM90: Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==VMCP/VCAP==
VMCP/VCAP: Vincristine, Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Salmon et al. 1983 (SWOG S7704)	1977-1979 	Phase 3 (E-esc-ic)	MP 	Longer OS
====Chemotherapy, VMCP portion (cycles 1, 3, 5)====
*Vincristine (Oncovin) 1 mg/m2 (maximum dose of 1.5 mg) IV once on day 1
*Melphalan (Alkeran) 6 mg/m2 PO once per day on days 1 to 4
*Cyclophosphamide (Cytoxan) 125 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy, VMCP portion (cycles 1, 3, 5)====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
====Chemotherapy, VCAP portion (cycles 2, 4, 6)====
*Vincristine (Oncovin) 1 mg/m2 (maximum dose of 1.5 mg) IV once on day 1
*Cyclophosphamide (Cytoxan) 125 mg/m2 PO once per day on days 1 to 4
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
====Glucocorticoid therapy, VCAP portion (cycles 2, 4, 6)====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
21-day cycle for 6 cycles (VMCP x 3; VCAP x 3)
===References===
# SWOG S7704: Salmon SE, Haut A, Bonnet JD, Amare M, Weick JK, Durie BG, Dixon DO. Alternating combination chemotherapy and levamisole improves survival in multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1983 Aug;1(8):453-61. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Consolidation after first-line therapy=
==Melphalan monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
McElwain & Powles 1983 	Not reported 	Pilot Study
Segeren et al. 2003 (HOVON 24)	1995-2000 	Non-randomized part of phase 3 RCT
Note that this is highly obsolete but included for historical interest. Stem cell rescue was NOT used.
====Preceding treatment====
*HOVON 24: Upfront VAD x 3 to 4
====Chemotherapy====
*Melphalan (Alkeran) 70 to 140 mg/m2 IV for one or more doses
====Subsequent treatment====
*HOVON 24: Cy/TBI with auto HSCT consolidation followed by interferon maintenance versus interferon maintenance
===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 EuroPMC
# HOVON 24: Segeren CM, Sonneveld P, van der Holt B, Vellenga E, Croockewit AJ, Verhoef GE, Cornelissen JJ, Schaafsma MR, van Oers MH, Wijermans PW, Fibbe WE, Wittebol S, Schouten HC, van Marwijk Kooy M, Biesma DH, Baars JW, Slater R, Steijaert MM, Buijt I, Lokhorst HM; HOVON. Overall and event-free survival are not improved by the use of myeloablative therapy following intensified chemotherapy in previously untreated patients with multiple myeloma: a prospective randomized phase 3 study. Blood. 2003 Mar 15;101(6):2144-51. Epub 2002 Nov 27. link to original article EuroPMC
## Update: Sonneveld P, van der Holt B, Segeren CM, Vellenga E, Croockewit AJ, Verhoe GE, Cornelissen JJ, Schaafsma MR, van Oers MH, Wijermans PW, Westveer PH, Lokhorst HM; HOVON. Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial. Haematologica. 2007 Jul;92(7):928-35. link to original article EuroPMC
==Melphalan monotherapy, then auto HSCT, then Melphalan & Busulfan, then auto HSCT==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cavo et al. 2007 (Bologna 96)	1996-2001 	Phase 3 (E-esc-ic)	Melphalan, then auto HSCT	Longer EFS (secondary endpoint)Median EFS: 35 vs 23 mo(HR not reported, p<0.001)Higher CR/nCR rate (primary composite endpoint)
===Consolidation, first transplant===
====Chemotherapy====
*Melphalan (Alkeran) 200 mg/m2 IV once on day -2
====Supportive therapy====
*Autologous stem cells re-infused on day 0
One course
===Consolidation, second transplant===
====Chemotherapy====
*Melphalan (Alkeran) 120 mg/m2 IV once on day -4
*Busulfan (Myleran) 4 mg/kg PO from day -5 to -3
====Supportive therapy====
*Autologous stem cells re-infused on day 0
One course
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==MEL200, then auto HSCT, then MEL220 & Dexamethasone, then auto HSCT==
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moreau et al. 2005 (IFM 99-04)	2000-2004 	Phase 3 (C)	MEL200, then MEL220 + Dex + B-E8	Did not meet primary endpoint of CR rate
Note: This protocol was meant for patients who did not have an HLA-identical sibling donor.
===Consolidation, first transplant===
====Preceding treatment====
*VAD induction x 4
====Chemotherapy====
*Melphalan (Alkeran) 200 mg/m2 IV once on day -2
====Supportive therapy====
*Autologous stem cells re-infused on day 0
One course
===Consolidation, second transplant===
====Chemotherapy====
*Melphalan (Alkeran) 220 mg/m2 IV once on day -2
====Glucocorticoid therapy, second transplant====
*Dexamethasone (Decadron) 40 mg (route not specified) over 4 days (days not specified)
====Supportive therapy====
*Autologous stem cells re-infused on day 0
One course
===References===
# IFM 99-04: 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. 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled 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. 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 EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
==Melphalan monotherapy, then auto HSCT, then Melphalan & TBI, then auto HSCT==
===Regimen variant #1, lower radiation===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Attal et al. 2003 (IFM94)	1994-1997 	Phase 3 (E-esc-ic)	MEL140-TBI & auto HSCT	Longer OSOS84: 42% vs 21%
====Preceding treatment====
*VAD induction x 3 to 4
====Chemotherapy====
*Melphalan (Alkeran) as follows:
**First transplant: 100 mg/m2 IV once per day on days -3 & -2
**Second transplant: 140 mg/m2 IV once on day -4
====Radiotherapy====
*Total body irradiation (TBI) as follows:
**Second transplant: 200 cGy fractions once per day x 4 = total dose of 800 cGy, without lung shielding
====Supportive therapy====
*Autologous stem cells re-infused on day 0
Two courses
====Subsequent treatment====
*Interferon alfa maintenance
===Regimen variant #2, higher radiation===
Study 	Dates of enrollment	Evidence
Barlogie et al. 1997 (Total Therapy 1)	1990-1994 	Non-randomized
Note: this regimen was intended for patients not achieving at least PR after the first transplant.
====Chemotherapy====
*Melphalan (Alkeran) as follows:
**First transplant: 100 mg/m2 IV once per day on days -3 & -2
**Second transplant: 140 mg/m2 IV once on day -4
====Radiotherapy====
*Total body irradiation (TBI) as follows: 
**Second transplant: 850 to 1020 cGy in 5 to 6 fractions delivered on days -3 to -1
====Supportive therapy====
*Autologous stem cells re-infused on day 0
Two courses
===References===
# Total Therapy 1: Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. link to original article EuroPMC
## Update: Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# IFM94: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
==Melphalan monotherapy, then auto HSCT, then Busulfan & Fludarabine, then allo HSCT==
===Protocol===
Study 	Dates of enrollment	Evidence
Garban et al. 2006 (IFM99-03)	2000-04 to 2004-09 	Non-randomized
Note: This regimen was meant for patients who had an HLA-identical sibling donor. 
====Preceding treatment====
*VAD induction x 4
====Chemotherapy, auto HSCT====
*Melphalan (Alkeran) 200 mg/m2 IV once on day -2
Stem cells re-infused on day 0, followed in two months by:
====Chemotherapy, allo HSCT====
===References===
# IFM99-03: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled 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. 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 EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
==Melphalan monotherapy, then auto HSCT, then TBI, then allo HSCT==
===Protocol===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bruno et al. 2007	1998-2004 	Pseudo-Mendelian randomization1	Tandem MEL-auto HSCT	Longer OS (co-primary endpoint)Median OS: 80 vs 54 mo(aHR 0.51, 95% CI 0.30-0.86)
1Randomization was based on the availability of an HLA-identical sibling.
====Preceding treatment====
*VAD induction
====Chemotherapy, auto HSCT====
*Melphalan (Alkeran) 200 mg/m2 IV once on day -2
====Supportive therapy====
*Autologous stem cells re-infused on day 0
One course, followed by:
====Radiotherapy, allo HSCT====
*TBI 200 cGy
====Immunotherapy====
*Allogeneic stem cells
====Supportive therapy====
*Autologous stem cells re-infused on day 0
One course
===References===
# 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 contains partial protocol EuroPMC NCT00415987
==Melphalan & Methylprednisolone, then auto HSCT==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Child et al. 2003 (MRC Myeloma VII)	1993-2000 	Phase 3 (E-esc-ic)	ABCM 	Seems to have longer OS (co-primary endpoint)Median OS: 54.1 vs 42.3 mo
====Preceding treatment====
*C-VAMP induction
====Chemotherapy====
*Melphalan (Alkeran) 200 mg/m2 IV once on day -1
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 1500 mg IV once per day on days 0 to +3 (4 doses)
====Supportive therapy====
*Autologous stem cells re-infused on day 0
One course
====Subsequent treatment====
*Interferon alfa maintenance
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Melphalan & TBI, then auto HSCT==
===Regimen variant #1, MEL140 & TBI 800 cGy===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Attal et al. 1996 (IFM90) 	1990-1993 	Phase 3 (E-esc-ic)	VMCP/VBAP x 18 	Seems to have longer OS
Barlogie et al. 2006 (SWOG S9321)	1993 to not reported	Phase 3 (E-esc-ic)	VBMCP 	Did not meet co-primary endpoints of ORR/OS
Attal et al. 2003 (IFM94) 	1994-1997 	Phase 3 (C) 	Melphalan, then auto HSCT, then Melphalan & TBI, then auto HSCT	Shorter OS
Moreau et al. 2002 (IFM 9502) 	1995-1999 	Phase 3 (C) 	High-dose melphalan & autologous transplant 	Might have shorter OS
====Preceding treatment====
*IFM90: VMCP alternating with VBAP induction x 4 to 6 cycles
*IFM 9502 and SWOG S9321: VAD induction x 3
*IFM94: VAD induction x 3 to 4
====Chemotherapy====
*Melphalan (Alkeran) 140 mg/m2 IV (day not specified)
====Radiotherapy====
*Total body irradiation (TBI) in 200 cGy fractions once per day x 4 = total dose of 800 cGy, without lung shielding
====Supportive therapy====
*Autologous stem cells re-infused on unspecified day
One course
====Subsequent treatment====
*Interferon alfa maintenance
===Regimen variant #2, MEL140 & TBI 1200 cGy===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Bladé et al. 2005	1994-1999 	Phase 3 (E-esc-ooc)	VBMCP/VBAD	Did not meet endpoints of PFS/OS1
1It is not clear from the manuscript what the primary endpoint was. While this regimen had lower CR rate, there was no difference in PFS or OS.
====Preceding treatment====
*VBMCP/VBAD induction x 4
====Chemotherapy====
*Melphalan (Alkeran) 140 mg/m2 IV once on day -2
====Radiotherapy====
*Total body irradiation (TBI) in 300 cGy fractions once per day on days -6 to -3 = total dose of 1200 cGy
====Supportive therapy====
*Autologous stem cells re-infused on day 0
One course
====Subsequent treatment====
*IFN & Dex maintenance
===References===
# IFM90: Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# IFM 9502: Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, François S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL; Intergroupe Francophone du Myélome. Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myélome 9502 randomized trial. Blood. 2002 Feb 1;99(3):731-5. link to original article EuroPMC
# IFM94: 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 EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; PETHEMA. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# SWOG S9321: 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 EuroPMC NCT00002548
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
=Maintenance after first-line therapy=
==Dexamethasone monotherapy==
===Regimen variant #1, 1 year===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Maiolino et al. 2012 (GBRAM0001)	2003-2008 	Phase 3 (C)	Thal-Dex 	Shorter PFS
====Preceding treatment====
*High-dose melphalan with autologous hematopoietic stem cell transplant consolidation
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycle for 13 cycles (1 year)
===Regimen variant #2, indefinite===
Study 	Dates of enrollment	Evidence
Cavo et al. 2010 (GIMEMA MM-BO2005)	2006-2008 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*TD versus VTD consolidation
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Supportive therapy====
*Acyclovir (Zovirax) prophylaxis recommended
28-day cycles
===References===
# GIMEMA MM-BO2005: Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01134484
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# GBRAM0001: 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. 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01296503
==Interferon alfa monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lokhorst et al. 2009 (HOVON-50)	2001-2005 	Phase 3 (C)	See link 	See link
Note: these trials do not specify an exact type of interferon alfa.
====Preceding treatment====
*HOVON-50: single or tandem melphalan auto HSCT consolidation
====Immunotherapy====
*Interferon alfa 3,000,000 IU SC once per day on days 1, 3, 5 (three times per week)
7-day cycles
===References===
# IFM90: Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R; Intergroupe Français du Myélome. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med. 1996 Jul 11;335(2):91-7. link to original article EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# 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 EuroPMC
# HOVON-50: Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00028886
## Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article EuroPMC
==Interferon alfa-2a monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Child et al. 2003 (MRC Myeloma VII)	1993-2000 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*ABCM vs intensive chemotherapy with HDM-auto HSCT consolidation
====Immunotherapy====
*Interferon alfa-2a (Roferon-A) 3,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
7-day cycles
===References===
# MRC Myeloma VII: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002599
==Interferon alfa-2b monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Mandelli et al. 1990 	1985-1988 	Phase 3 (E-esc)	Observation 	Might have longer OS
Browman et al. 1995 	1987-1992 	Phase 3 (E-esc)	Observation 	Seems to have longer OS
Schaar et al. 2005 (HOVON-16) 	1991-1997 	Phase 3 (E-esc)	Observation 	Longer PFS
Ludwig et al. 2008 (01-002-0601) 	2001-2007 	Phase 3 (C) 	Interferon alfa-2b & Thalidomide	Shorter PFS
Rosiñol et al. 2012 (GEM05/MENOS65)	2006-2009 	Phase 3 (C) 	1. Thalidomide 	Not reported
Rosiñol et al. 2012 (GEM05/MENOS65)	2006-2009 	Phase 3 (C) 	2. VT 	Seems to have shorter PFS1
1Reported efficacy for GEM05/MENOS65 is based on the 2017 update.
====Preceding treatment====
*Mandelli et al. 1990: Induction MP x 12 mo or VMCP/VBAP x 12 mo
*Browman et al. 1995 & HOVON-16: Induction MP
*01-002-0601: MP vs TD induction
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 3,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
7-day cycles
===References===
# Mandelli F, Avvisati G, Amadori S, Boccadoro M, Gernone A, Lauta VM, Marmont F, Petrucci MT, Tribalto M, Vegna ML, Dammacco F, Pileri A. Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med. 1990 May 17;322(20):1430-4. link to original article EuroPMC
# Browman GP, Bergsagel D, Sicheri D, O'Reilly S, Wilson KS, Rubin S, Belch A, Shustik C, Barr R, Walker I, James K, Zee B, Johnston D; National Cancer Institute of Canada Clinical Trials Group. Randomized trial of interferon maintenance in multiple myeloma: a study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1995 Sep;13(9):2354-60. link to original article EuroPMC
# SWOG 9028: Salmon SE, Crowley JJ, Balcerzak SP, Roach RW, Taylor SA, Rivkin SE, Samlowski W. Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1998 Mar;16(3):890-6. link to original article EuroPMC
# HOVON-16: Schaar CG, Kluin-Nelemans HC, Te Marvelde C, le Cessie S, Breed WP, Fibbe WE, van Deijk WA, Fickers MM, Roozendaal KJ, Wijermans PW; HOVON. Interferon-alpha as maintenance therapy in patients with multiple myeloma. Ann Oncol. 2005 Apr;16(4):634-9. Epub 2005 Mar 1. link to original article EuroPMC
# 01-002-0601: Ludwig H, Hajek R, Tóthová E, Drach J, Adam Z, Labar B, Egyed M, Spicka I, Gisslinger H, Greil R, Kuhn I, Zojer N, Hinke A. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood. 2009 Apr 9;113(15):3435-42. Epub 2008 Oct 27. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00205751
## Update: 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 link to PMC article EuroPMC
# GEM05/MENOS65: Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; PETHEMA; GEM. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00461747
## Update: Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Interferon alfa & Dexamethasone==
===Regimen===
Study 	Dates of enrollment	Evidence
Bladé et al. 2005	1994-1999 	Non-randomized part of phase 3 RCT
Note: this study did not specify an exact type of interferon alfa.
====Preceding treatment====
*VBMCP/VBAD induction x 4 followed by HDT with MEL200 with auto HSCT or MEL140 & TBI with auto HSCT consolidation versus VBMCP/VBAD induction x 12
====Immunotherapy====
*Interferon alfa 3,000,000 units SC once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 (3 times per week)
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles
===References===
# Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; PETHEMA. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005 Dec 1;106(12):3755-9. Epub 2005 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Interferon alfa-2b & Prednisone==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Salmon et al. 1998 (SWOG 9028)	1990-1993 	Phase 3 (E-esc-ooc)	Interferon alfa-2b	Longer PFS
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 3,000,000 units SC once per day on days 1, 3, 5
====Glucocorticoid therapy====
*Prednisone (Sterapred) 50 mg PO once per day on days 2, 4, 6
7-day cycles
===References===
# SWOG 9028: Salmon SE, Crowley JJ, Balcerzak SP, Roach RW, Taylor SA, Rivkin SE, Samlowski W. Interferon versus interferon plus prednisone remission maintenance therapy for multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol. 1998 Mar;16(3):890-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Interferon alfa-2b & Thalidomide==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ludwig et al. 2008 (01-002-0601)	2001-2007 	Phase 3 (E-esc-ooc)	Interferon alfa-2b	Longer PFS (primary endpoint)
====Immunotherapy====
*Interferon alfa-2b (Intron-A) 3,000,000 units SC once per day on days 1, 3, 5 (3 times per week)
====Targeted therapy====
*Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 7
7-day cycles
===References===
# 01-002-0601: Ludwig H, Hajek R, Tóthová E, Drach J, Adam Z, Labar B, Egyed M, Spicka I, Gisslinger H, Greil R, Kuhn I, Zojer N, Hinke A. Thalidomide-dexamethasone compared with melphalan-prednisolone in elderly patients with multiple myeloma. Blood. 2009 Apr 9;113(15):3435-42. Epub 2008 Oct 27. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00205751
## Update: 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 link to PMC article EuroPMC
==Prednisolone monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Spencer et al. 2009 (ALLG MM6)	2002-2005 	Phase 3 (C)	Thalidomide & Prednisolone	Shorter OSOS60: 47% vs 66%(HR 8.33, 95% CI 1.79-33.33)
====Preceding treatment====
*High-dose melphalan & auto HSCT consolidation
====Glucocorticoid therapy====
*Prednisolone (Millipred) 50 mg PO once every other day 
Continued indefinitely
===References===
# ALLG MM6: Spencer A, Prince HM, Roberts AW, Prosser IW, Bradstock KF, Coyle L, Gill DS, Horvath N, Reynolds J, Kennedy N. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009 Apr 10;27(11):1788-93. Epub 2009 Mar 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ACTRN12607000382471
## Subgroup analysis: Ho PJ, Brown RD, Spencer A, Jeffels M, Daniher D, Gibson J, Joshua DE. Thalidomide consolidation improves progression-free survival in myeloma with normal but not up-regulated expression of fibroblast growth factor receptor 3: analysis from the Australasian Leukaemia and Lymphoma Group MM6 clinical trial. Leuk Lymphoma. 2012 Sep;53(9):1728-34. Epub 2012 Mar 13. link to original article EuroPMC
## Update: Kalff A, Kennedy N, Smiley A, Prince HM, Roberts AW, Bradstock K, De Abreu Lourenço R, Frampton C, Spencer A. Thalidomide and prednisolone versus prednisolone alone as consolidation therapy after autologous stem-cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the ALLG MM6 multicentre, open-label, randomised phase 3 study. Lancet Haematol. 2014 Dec;1(3):e112-9. Epub 2014 Dec 1. link to original article EuroPMC
==Prednisone monotherapy==
===Regimen variant #1, high-dose===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Berenson et al. 2002 (SWOG 9210)	1993-1997 	Phase 3 (E-esc-ic)	Prednisone; low-dose	Seems to have longer OS
====Preceding treatment====
*VAD-P versus VAD-P/Q induction
====Glucocorticoid therapy====
*Prednisone (Sterapred) 50 mg PO once every other day 
Continued indefinitely
===Regimen variant #2, low-dose===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Berenson et al. 2002 (SWOG 9210)	1993-1997 	Phase 3 (E-de-esc)	Prednisone; high-dose	Seems to have shorter OS
====Preceding treatment====
*VAD-P versus VAD-P/Q induction
====Glucocorticoid therapy====
*Prednisone (Sterapred) 10 mg PO once every other day 
Continued indefinitely
===References===
# SWOG 9210: Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
=Relapsed or refractory=
==Belantamab mafodotin monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Lonial et al. 2019 (DREAMM-2) 	2018-2019 	Phase 2 (RT) 	 	
Dimopoulos et al. 2023 (DREAMM-3)	2020-04-02 to 2022-04-18	Phase 3 (E-switch-ooc)	Pd 	Did not meet primary endpoint of PFSMedian PFS: 11.2 vs 7 mo(HR 1.03, 95% CI 0.72-1.47)
Note: while DREAMM-2 was a randomized trial, it was not comparative between the arms. The results of DREAMM-3 were negative and were the basis of withdrawal of FDA accelerated approval in 2023.
====Antibody-drug conjugate therapy====
*Belantamab mafodotin (Blenrep) 2.5 mg/kg IV over 30 minutes once on day 1
21-day cycles
===References===
#DREAMM-2: Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AO, Callander N, Lendvai N, Sborov D, Suvannasankha A, Weisel K, Karlin L, Libby E, Arnulf B, Facon T, Hulin C, Kortüm KM, Rodríguez-Otero P, Usmani SZ, Hari P, Baz R, Quach H, Moreau P, Voorhees PM, Gupta I, Hoos A, Zhi E, Baron J, Piontek T, Lewis E, Jewell RC, Dettman EJ, Popat R, Esposti SD, Opalinska J, Richardson P, Cohen AD. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020 Feb;21(2):207-221. Epub 2019 Dec 16. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03525678
##Update: Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AO, Callander N, Sborov D, Suvannasankha A, Weisel K, Voorhees PM, Womersley L, Baron J, Piontek T, Lewis E, Opalinska J, Gupta I, Cohen AD. Longer term outcomes with single-agent belantamab mafodotin in patients with relapsed or refractory multiple myeloma: 13-month follow-up from the pivotal DREAMM-2 study. Cancer. 2021 Nov 15;127(22):4198-4212. Epub 2021 Jul 27. link to original article link to PMC article EuroPMC
# DREAMM-3: Dimopoulos MA, Hungria VTM, Radinoff A, Delimpasi S, Mikala G, Masszi T, Li J, Capra M, Maiolino A, Pappa V, Chraniuk D, Osipov I, Leleu X, Low M, Matsumoto M, Sule N, Li M, McKeown A, He W, Bright S, Currie B, Perera S, Boyle J, Roy-Ghanta S, Opalinska J, Weisel K. Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study. Lancet Haematol. 2023 Oct;10(10):e801-e812. link to original article EuroPMC NCT04162210
==Bortezomib monotherapy==
===Regimen variant #1, 1 mg/m2, 21-day cycle x 8===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Jagannath et al. 2004 (CREST) 	2001-2002 	Randomized Phase 2 (E-de-esc)	Bortezomib +/- Dexamethasone; 1.3 mg/m2	Did not meet primary endpoint of ORR
Petrucci et al. 2013 (RETRIEVE)	2006 to not reported	Phase 2 (RT) 	 	
Note: RETRIEVE was a re-treatment trial; the dose used was the same as in the initial treatment (1.0 or 1.3 mg/m2).
====Prior treatment criteria====
*CREST: 1 to 3 prior therapies, not including bortezomib
====Targeted therapy====
*Bortezomib (Velcade) 1 mg/m2 IV bolus once per day on days 1, 4, 8, 11
21-day cycle for 8 cycles
====Subsequent treatment====
*CREST, patients with PD after 2 cycles or SD after 4 cycles: Optional intensification to bortezomib & dexamethasone
===Regimen variant #2, 1.3 mg/m2, 21-day cycle x 8 (IV)===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Jagannath et al. 2004 (CREST) 	2001-2002 	Randomized Phase 2 (E-esc-ic)	Bortezomib +/- Dexamethasone; 1 mg/m2	Did not meet primary endpoint of ORR
Richardson et al. 2005 (APEX) 	2002-06 to 2003-10 	Phase 3 (E-RT-switch-ooc) 	High-dose dexamethasone 	Seems to have longer OS1 (secondary endpoint)(HR 0.77)
Petrucci et al. 2013 (RETRIEVE)	2006 to not reported	Phase 2 (RT) 	 	
White et al. 2012 (AMBER) 	2007-2009 	Randomized Phase 2 (C) 	Bortezomib & Bevacizumab 	Did not meet primary endpoint of PFS
Moreau et al. 2011 (MMY-3021) 	2008-2010 	Phase 3 (C) 	Bortezomib +/- Dexamethasone; SC 	Non-inferior ORR after 4 cycles (primary endpoint)
1Reported efficacy for APEX is based on the 2007 update.
Note: RETRIEVE was a re-treatment trial; the dose used was the same as in the initial treatment (1.0 or 1.3 mg/m2).
====Prior treatment criteria====
*CREST: 1 to 3 prior therapies, not including bortezomib
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
====Supportive therapy====
*Bisphosphonate IV therapy once every 3 to 4 weeks unless contraindicated
21-day cycle for 8 cycles
====Subsequent treatment====
*CREST, patients with PD after 2 cycles or SD after 4 cycles: Optional intensification to bortezomib & dexamethasone
*APEX: Bortezomib consolidation
*MMY-3021, patients with suboptimal response after 4 cycles: Optional intensification to bortezomib & dexamethasone
*MMY-3021, patients who were "evolving" towards CR after 8 cycles: Optional bortezomib continuation x 2 additional cycles (10 total)
===Regimen variant #3, 1.3 mg/m2, 21-day cycle x 8 (SC)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Moreau et al. 2011 (MMY-3021)	2008-2010 	Phase 3 (E-RT-switch-ic)	Bortezomib +/- Dexamethasone; IV	Non-inferior ORR after 4 cycles (primary endpoint)
====Targeted therapy====
*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 
====Supportive therapy====
*Bisphosphonates "according to established guidelines"
21-day cycle for 8 cycles (see note)
====Subsequent treatment====
*MMY-3021, patients with suboptimal response after 4 cycles could escalate to: bortezomib & dexamethasone
*MMY-3021, patients who were "evolving" towards CR after 8 cycles could receive: 2 additional cycles
===Regimen variant #4, 1.3 mg/m2, 21-day cycle x 8, then 35-day cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Orlowski et al. 2015 (CR012784)	2006-2009 	Randomized Phase 2 (C)	Bortezomib & Siltuximab	Did not meet primary endpoint of PFS
====Targeted therapy====
*Bortezomib (Velcade) as follows:
**Cycles 1 to 8: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
**Cycle 9 onwards: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
21-day cycle for 8 cycles, then 35-day cycles
===Regimen variant #5, indefinite 21-day cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Richardson et al. 2003 (SUMMIT) 	2001-02 to 2001-12 	Phase 2 (RT)	 	
Orlowski et al. 2007 (MMY-3001) 	2004-2006 	Phase 3 (C) 	Bortezomib & PLD 	Shorter TTPMedian TTP: 6.5 vs 9.3 mo(HR 1.82, 95% CI 1.41-2.33)
Dimopoulos et al. 2013 (VANTAGE 088)	2008-2011 	Phase 3 (C) 	Bortezomib & Vorinostat	Shorter PFSMedian PFS: 6.8 vs 7.6 mo(HR 1.30, 95% CI 1.06-1.56)
Note: SUMMIT and MMY-3001 specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
21-day cycles (see note)
====Subsequent treatment====
*SUMMIT & MMY-3001, patients with PD after 2 cycles or SD after 4 cycles: Optional intensification to bortezomib & dexamethasone
===Regimen variant #6, 1.6 mg/m2, 35-day cycle x 10===
Study 	Dates of enrollment	Evidence
Hainsworth et al. 2008	2004-2006 	Phase 2
====Targeted therapy====
*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===
# SUMMIT: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 dosing details in abstract have been reviewed by our editors EuroPMC 
## Pooled subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article EuroPMC
# CREST: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 dosing details in abstract have been reviewed by our editors EuroPMC 
## 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 EuroPMC
# APEX: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00048230
## Pooled subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article EuroPMC
## Update: Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San Miguel J, 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# MMY-3001: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00103506
## Update: 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# MMY-3021: 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):431-40. Epub 2011 Apr 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00722566
## 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 link to PMC article EuroPMC
## 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 link to PMC article EuroPMC
# AMBER: White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE. Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. Cancer. 2013 Jan 15;119(2):339-47. Epub 2012 Jul 18. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00473590
# RETRIEVE: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00431769
# VANTAGE 088: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00773747
# CR012784: 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 original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00401843
==Carmustine & Doxorubicin==
===Regimen===
Study 	Dates of enrollment	Evidence
Alberts et al. 1976	1974-1975 	Non-randomized, fewer than 20 pts
====Chemotherapy====
*Carmustine (BCNU) 30 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
21- to 28-day cycles
===References===
# Alberts DS, Durie BG, Salmon SE. Doxorubicin/BCNU chemotherapy for multiple myeloma in relapse. Lancet. 1976 May 1;1(7966):926-8. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==Cyclophosphamide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cook et al. 2014 (NCRI Myeloma X Relapse)	2008-2012 	Phase 3 (C)	Mel-auto HSCT	Shorter TTP
====Preceding treatment====
*Salvage PAD x 4
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 400 mg/m2 PO once on day 1
7-day cycle for 12 cycles
===References===
# NCRI Myeloma X Relapse: Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00747877
## Update: 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 EuroPMC
## Subgroup analysis: Cook G, Royle KL, O'Connor S, Cairns DA, Ashcroft AJ, Williams CD, Hockaday A, Cavenagh JD, Snowden JA, Ademokun D, Tholouli E, Andrews VE, Jenner M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Drayson MT, Brown JM, Morris TCM; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Br J Haematol. 2019 May;185(3):450-467. Epub 2019 Feb 6. link to original article link to PMC article EuroPMC
==Dexamethasone monotherapy==
===Regimen variant #1, indefinite, high-dose===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Chanan-Khan et al. 2009 (GENTA-GMY302)	2001-2003 	Phase 3 (C)	Oblimersen & Dexamethasone	Did not meet primary endpoint of TTP
San Miguel et al. 2013 (NIMBUS) 	2011-03-18 to 2012-08-30	Phase 3 (C)	PD 	Shorter OS1
1Reported efficacy reported for NIMBUS is based on the 2015 update.
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
7-day cycles
===Regimen variant #2, indefinite, weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Spicka et al. 2019 (ADMYRE)	2010-2015 	Phase 3 (C)	Plitidepsin & Dexamethasone	Shorter PFS
====Prior treatment criteria====
*3 to 6 prior lines of therapy, including at least bortezomib and lenalidomide or thalidomide
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once on day 1
7-day cycles
===Regimen variant #3, indefinite, with de-escalation===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Weber et al. 2007 (MM-009) 	2003-02-27 to 2004-04-14	Phase 3 (C)	RD 	Seems to have shorter OS1
Dimopoulos et al. 2007 (MM-010)	2003-09-22 to 2004-09-15	Phase 3 (C)	RD 	Seems to have shorter OS
1Reported efficacy of MM-009 is based on the 2009 pooled update.
====Glucocorticoid therapy====
*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 variant #4, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Richardson et al. 2005 (APEX)	2002-06 to 2003-10 	Phase 3 (C)	Bortezomib	Seems to have shorter OS1
1Reported efficacy is based on the 2007 update.
====Glucocorticoid therapy====
*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 
**Cycles 5 to 9: 40 mg PO once per day on days 1 to 4
35-day cycle for 4 cycles, then 28-day cycle for 4 cycles
===Regimen variant #5, 12 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kropff et al. 2011 (OPTIMUM)	2006-2009 	Phase 3 (C)	1. Thalidomide; 100 mg/d2. Thalidomide; 200 mg/d 3. Thalidomide; 400 mg/d	Did not meet primary endpoint of TTP
====Glucocorticoid therapy====
*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 
**Cycles 5 to 12: 40 mg PO once per day on days 1 to 4
28-day cycle for up to 12 cycles
===References===
# APEX: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00048230
## Pooled subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article EuroPMC
## 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 EuroPMC
# MM-010: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00424047
## Pooled 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 EuroPMC
# MM-009: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00056160
## Pooled 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 EuroPMC
# GENTA-GMY302: Chanan-Khan AA, Niesvizky R, Hohl RJ, Zimmerman TM, Christiansen NP, Schiller GJ, Callander N, Lister J, Oken M, Jagannath S. Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma. Leuk Lymphoma. 2009 Apr;50(4):559-65. link to original article EuroPMC NCT00017602
# OPTIMUM: Kropff M, Baylon HG, Hillengass J, Robak T, Hajek R, Liebisch P, Goranov S, Hulin C, Bladé J, Caravita T, Avet-Loiseau H, Moehler TM, Pattou C, Lucy L, Kueenburg E, Glasmacher A, Zerbib R, Facon T. Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial. Haematologica. 2012 May;97(5):784-91. Epub 2011 Dec 1. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00452569
# NIMBUS: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01311687
##HRQoL analysis: Weisel K, Dimopoulos M, Song KW, Moreau P, Palumbo A, Belch A, Schey S, Sonneveld P, Sternas L, Yu X, Amatya R, Gibson CJ, Zaki M, Jacques C, San Miguel J. Pomalidomide and Low-Dose Dexamethasone Improves Health-Related Quality of Life and Prolongs Time to Worsening in Relapsed/Refractory Patients With Multiple Myeloma Enrolled in the MM-003 Randomized Phase III Trial. Clin Lymphoma Myeloma Leuk. 2015 Sep;15(9):519-30. Epub 2015 Jun 6. link to original article EuroPMC
## 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 link to PMC article EuroPMC
# ADMYRE: Spicka I, Ocio EM, Oakervee HE, Greil R, Banh RH, Huang SY, D'Rozario JM, Dimopoulos MA, Martínez S, Extremera S, Kahatt C, Alfaro V, Carella AM, Meuleman N, Hájek R, Symeonidis A, Min CK, Cannell P, Ludwig H, Sonneveld P, Mateos MV. Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs dexamethasone alone in patients with relapsed/refractory multiple myeloma. Ann Hematol. 2019 Sep;98(9):2139-2150. Epub 2019 Jun 25. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT01102426
==DECA==
DECA: Dexamethasone, Etoposide, Cisplatin, Ara-C (Cytarabine)
EDAP: Etoposide, Dexamethasone, Ara-C (Cytarabine), Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence
Barlogie et al. 1989	Not reported 	Non-randomized
====Chemotherapy====
*Etoposide (Vepesid) 100 to 200 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 400 to 800 mg/m2)
*Cytarabine (Ara-C) 1000 mg IV once on day 5
*Cisplatin (Platinol) 20 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 80 mg/m2)
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 5
21- to 28-day cycles
===References===
# Barlogie B, Velasquez WS, Alexanian R, Cabanillas F. Etoposide, dexamethasone, cytarabine, and cisplatin in vincristine, doxorubicin, and dexamethasone-refractory myeloma. J Clin Oncol. 1989 Oct;7(10):1514-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Pomalidomide, Dexamethasone, Pembrolizumab==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Badros et al. 2017 (1454GCC)	2015-2016 	Phase 2 	ORR: 60%
Note: This is of historical interest only, at this time. While the phase 2 had a high degree of efficacy (thus meeting our inclusion criteria), subsequent phase 3 trials were halted by the FDA for excess deaths in this arm; see "Note added in proof" in the paper for more details.
====Targeted therapy====
*Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**70 years old or younger: 40 mg PO once per day on days 1, 8, 15, 22
**Older than 70 years old: 20 mg PO once per day on days 1, 8, 15, 22
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once per day on days 1 & 15
28-day cycle for 26 cycles
===References===
# 1454GCC: Badros A, Hyjek E, Ma N, Lesokhin A, Dogan A, Rapoport AP, Kocoglu M, Lederer E, Philip S, Milliron T, Dell C, Goloubeva O, Singh Z. Pembrolizumab, pomalidomide, and low-dose dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1189-1197. Epub 2017 May 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02289222
==Stilbamidine & Urethane==
===Regimen===
Study 	Evidence
Alwall 1947	Case series
====Chemotherapy====
*Stilbamidine
*Urethane
===References===
#Case series: Alwall N. Urethane and stilbamidine in multiple myeloma report on two cases. Lancet. 1947 Sep 13;2(6472):388. link to original article EuroPMC
==Tisagenlecleucel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Garfall et al. 2015 (UPCC02413)	2014 	Pilot, 1 patient
Note: this regimen is of historic interest in this context. It is not FDA approved for this indication.
====Immunotherapy====
*Tisagenlecleucel (Kymriah) 
===References===
# UPCC02413: Garfall AL, Maus MV, Hwang WT, Lacey SF, Mahnke YD, Melenhorst JJ, Zheng Z, Vogl DT, Cohen AD, Weiss BM, Dengel K, Kerr ND, Bagg A, Levine BL, June CH, Stadtmauer EA. Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med. 2015 Sep 10;373(11):1040-7. link to original article link to PMC article EuroPMC NCT02135406
==Urethane monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Luttgens et al. 1951	1948-1950 	Case series 	 	
Holland et al. 1966 	1958-1961 	Randomized (E-esc)	Placebo 	Seems to have shorter OS
====Chemotherapy====
*Urethane
===References===
# Luttgens WF, Bayrd ED. Treatment of multiple myeloma with urethan: experience with sixty-six cases over a two-and-a-half-year period. JAMA. 1951 Oct;147(9):824-7. link to original article EuroPMC
#Holland JF, Hosley H, Scharlau C, Carbone PP, Frei E 3rd, Brindley CO, Hall TC, Shnider BI, Gold GL, Lasagna L, Owens AH Jr, Miller SP. A controlled trial of urethane treatment in multiple myeloma. Blood. 1966 Mar;27(3):328-42. link to original article EuroPMC
==VAD==
VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
VAd: Vincristine, Adriamycin (Doxorubicin), low-dose dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Barlogie et al. 1984 	1983 	Phase 2 	 	
Dalton et al. 1995 (SWOG S8900)	1988-1991 	Phase 3 (C)	VAD/v 	Did not meet endpoints of ORR/OS
Note: Treatment was given "until a maximum reduction in myeloma protein had occurred" and patients received four additional cycles of therapy beyond their best response.
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
====Supportive therapy====
*Cimetidine (Tagamet) prophylaxis (dose not specified)
*Trimethoprim/Sulfamethoxazole prophylaxis (dose not specified)
35-day cycles (see note)
===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 dosing details in manuscript have been reviewed by our editors EuroPMC
# SWOG S8900: Dalton WS, Crowley JJ, Salmon SS, Grogan TM, Laufman LR, Weiss GR, Bonnet JD. A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma: a Southwest Oncology Group study. Cancer. 1995 Feb 1;75(3):815-20. link to original article EuroPMC
==VAD & Cyclosporine==
VAD & Cyclosporine: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Cyclosporine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Sonneveld et al. 1992 	Not reported 	Non-randomized 	 	
Sonneveld et al. 2001 (EORTC 06914)	Not reported 	Phase 2/3 (E-esc-ooc)	VAD 	Did not meet primary endpoint of best RR
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg)
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2
====Glucocorticoid therapy====
*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
====Immunosuppressive therapy====
*Cyclosporine 2 mg/kg IV once on day 1, given 2 hours before VAD, then 7.5 mg/kg/day IV continuous infusion over 96 hours
28-day cycle for 4 cycles
===References===
# Sonneveld P, Durie BG, Lokhorst HM, Marie JP, Solbu G, Suciu S, Zittoun R, Löwenberg B, Nooter K; EORTC; HOVON. Modulation of multidrug-resistant multiple myeloma by cyclosporin. Lancet. 1992 Aug 1;340(8814):255-9. link to original article EuroPMC
# EORTC 06914: Sonneveld P, Suciu S, Weijermans P, Beksac M, Neuwirtova R, Solbu G, Lokhorst H, van der Lelie J, Dohner H, Gerhartz H, Segeren CM, Willemze R, Lowenberg B; EORTC; Leukaemia Cooperative Group; HOVON. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br J Haematol. 2001 Dec;115(4):895-902. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
Category:Multiple myeloma regimens
Category:Historical regimens
Category:Disease-specific pages
Category:Plasma cell dyscrasias