Staging page

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? Please go to the main multiple myeloma regimen page to find other regimens.

0 regimens on this page 0 variants on this page

First-line therapy

ABCM

ABCM: Adriamycin (Doxorubicin), BCNU (Carmustine), Cyclophosphamide, Melphalan

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
MacLennan et al. 1992 (MRC Myeloma V)	1982-1986	Phase 3 (E-esc-ic)	Melphalan	Superior OS Median OS: 32 vs 24 mo
Child et al. 2003 (MRC Myeloma VII)	1993-2000	Phase 3 (C)	C-VAMP	Seems to have inferior OS

Chemotherapy

• Doxorubicin (Adriamycin)
• Carmustine (BCNU)
• Cyclophosphamide (Cytoxan)
• Melphalan (Alkeran)

References

1. 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 PubMed
2. 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 PubMed NCT00002599
3. MRC Myeloma VIII: NCT00002653

BiRd

BiRd: Biaxin (Clarithromycin), Revlimid (Lenalidomide), low-dose dexamethasone
C-Rd: Clarithromycin, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Years 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 PFS Median 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

1. Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S, Jalbrzikowski J, Pearse RN, Zafar F, Pekle K, Larow A, Lent R, Mark T, Cho HJ, Shore T, Tepler J, Harpel J, Schuster MW, Mathew S, Leonard JP, Mazumdar M, Chen-Kiang S, Coleman M. BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete- and overall-response rates in treatment-naive symptomatic multiple myeloma. Blood. 2008 Feb 1;111(3):1101-9. Epub 2007 Nov 7. link to original article contains dosing details in abstract PubMed NCT00151203
   1. Update: Rossi A, Mark T, Jayabalan D, Christos P, Zafar F, Pekle K, Pearse R, Chen-Kiang S, Coleman M, Niesvizky R. BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma. Blood. 2013 Mar 14;121(11):1982-1985. Epub 2013 Jan 8. link to original article contains dosing details in abstract link to PMC article PubMed
2. Retrospective: Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. link to original article contains dosing details in abstract link to PMC article PubMed
3. 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 PubMed NCT02575144

mCOP/MP

mCOP/MP: modified Cyclophosphamide, Oncovin (Vincristine), Prednisolone alternating with Melphalan & Prednisolone

Regimen

Study	Years 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

1. 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 contains dosing details in manuscript PubMed

C-VAMP

C-VAMP: Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), MethylPrednisolone

Regimen

Study	Years 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 superior OS

A minimum of 3 cycles were given before stem cell harvest.

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg IV once per day on days 1, 8, 15
  • Cyclophosphamide was omitted in patients with a serum creatinine greater than 3.4 mg/dL
• 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

References

1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed NCT00002599

Cyclophosphamide monotherapy

Regimen

Study	Years of enrollment	Evidence
Korst et al. 1964	NR-1963	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan) 2 mg/kg PO once per day

Continued indefinitely

References

1. 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 contains dosing details in manuscript PubMed

CVP

CVP: Cyclophosphamide, Vincristine, Prednisone
VCP: Vincristine, Cyclophosphamide, Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Durie et al. 1986 (SWOG S7927/S7928)	1979-1982	Phase 3 (C)	VMCP/VBAP	Seems to have inferior 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

References

1. 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 contains dosing details in manuscript PubMed

Dexamethasone monotherapy

Regimen variant #1, 35-day cycles

Study	Years 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
  • Non-responders: unclear from manuscript

Regimen variant #2, indefinite with 35-day induction cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Zonder et al. 2010 (SWOG S0232)	2004-2007	Phase 3 (C)	Len-Dex	Inferior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rajkumar et al. 2008 (THAL-MM-003)	2003-2005	Phase 3 (C)	TD	Inferior TTP

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Rajkumar et al. 2005 (ECOG E1A00)	NR	Phase 3 (C)	TD	Seems to have inferior RR	Superior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Facon et al. 2005 (IFM 95-01)	1995-1998	Phase 3 (E-de-esc)	1. DEX-IFN 2. 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

1. 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 contains dosing details in manuscript PubMed
2. 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 contains dosing details in manuscript PubMed
3. 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 contains dosing details in abstract PubMed
4. 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 contains dosing details in abstract PubMed NCT00033332
5. 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 contains dosing details in manuscript link to PMC article PubMed NCT00057564
6. 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 contains dosing details in manuscript PubMed NCT00064038

DEX-IFN

DEXamethasone, InterFeroN alfa-2b

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Facon et al. 2005 (IFM 95-01)	1995-1998	Phase 3 (E-de-esc)	1. Dexamethasone 2. 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

1. 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 contains dosing details in abstract PubMed

EDAP

EDAP: Etoposide, Dexamethasone, Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study	Years of enrollment	Evidence
Barlogie et al. 1997 (Total Therapy 1)	1990-1994	Non-randomized

Given as a component of Total Therapy.

Chemotherapy

• Etoposide (Vepesid)
• Cytarabine (Ara-C)
• Cisplatin (Platinol)

Glucocorticoid therapy

• Dexamethasone (Decadron)

References

1. 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 PubMed
   1. 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 contains dosing details in manuscript PubMed
   2. 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 PubMed

Lenalidomide & Dexamethasone (RD)

RD: Revlimid (Lenalidomide) & high-dose Dexamethasone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rajkumar et al. 2009 (ECOG E4A03)	2004-2006	Phase 3 (C)	Rd	Inferior 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

• Responding patients could choose after 4 cycles to proceed to high-dose melphalan with autologous hematopoietic stem cell transplant or to continue RD until progression of disease or intolerable toxicity
• Non-responders were transitioned to Thal-Dex (details not described)

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00098475
   1. 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 PubMed

Melphalan monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bergsagel et al. 1965	NR in abstract	Non-randomized
Hoogstraten et al. 1967	NR	Non-randomized portion of RCT
Rivers & Patno 1969	1960-1962	Phase 3 (E-switch-ic)	Cyclophosphamide	Did not meet endpoint of OS
Hoogstraten et al. 1969a	NR	Non-randomized

Chemotherapy

• Melphalan (Alkeran)

References

1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed

M-DEX

M-DEX: Melphalan & DEXamethasone
MD: Melphalan & Dexamethasone

Regimen variant #1, 0.25/40

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Facon et al. 2005 (IFM 95-01)	1995-1998	Phase 3 (E-esc-ic)	1. Dexamethasone 2. MP 3. 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hernández et al. 2004 (MM-PETHEMA 96)	1997-NR	Phase 3 (E-switch-ic)	MP	Did not meet endpoints of ORR/OS

Note: this is 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

1. 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 contains dosing details in manuscript PubMed
2. 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 contains dosing details in manuscript PubMed

Melphalan & Prednisone (MP)

MP: Melphalan & Prednisone

Regimen variant #1, melphalan 0.15 mg/kg

Study	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Palumbo et al. 2012 (MM-015)	2007-2008	Phase 3 (C)	1. MPR	Did not meet primary endpoint of PFS
			2. MPR-R	Inferior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hulin et al. 2009 (IFM 01/01)	2002-2006	Phase 3 (C)	MPT	Seems to have inferior OS

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	Years 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. Dexamethasone 2. 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	Inferior OS
			2. VAD, then MEL100	Did not meet primary endpoint of OS

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 (SWG01)

Regimen variant #5, melphalan 0.25 mg/kg x 4 d/cycle, flat dose prednisone

Study	Years 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

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wijermans et al. 2010 (HOVON 49)	2002-2007	Phase 3 (C)	MP-T	Might have inferior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Palumbo et al. 2006 (GISMM2001-A)	2002-2005	Phase 3 (C)	MPT	Seems to have inferior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
San Miguel et al. 2008 (VISTA)	2004-2006	Phase 3 (C)	VMP	Inferior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Beksac et al. 2010 (TMSG-2005-001)	2006-2009	Phase 3 (C)	MPT	Seems to have inferior 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	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bergsagel et al. 1979	1973-1977	Phase 3 (C)	1. B/C/M 2. BCM	Did not meet primary endpoint of OS
Hernández et al. 2004 (MM-PETHEMA 96)	1997-NR	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
  • Hernández et al. 2004: 60 mg/m² PO once per day on days 1 to 4

28-day cycles

Regimen variant #12, melphalan 15 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Pönisch et al. 2006	1994-1999	Phase 3 (C)	BP	Inferior 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

References

1. 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 contains dosing details in manuscript PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed
5. 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 PubMed
6. Review: Myeloma Trialists' Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol. 1998 Dec;16(12):3832-42. link to original article contains dosing details in abstract PubMed
7. 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 contains dosing details in manuscript PubMed
8. 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 contains dosing details in manuscript PubMed
9. 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 contains dosing details in abstract PubMed NCT00232934
   1. Update: Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. link to original article contains dosing details in abstract PubMed
10. 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 contains dosing details in manuscript PubMed
11. 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 contains dosing details in manuscript PubMed NCT00002678
12. 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 contains dosing details in abstract PubMed content property of HemOnc.org NCT00367185
13. 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 contains dosing details in manuscript PubMed NCT00111319
    1. Update: Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010 May 1;28(13):2259-66. Epub 2010 Apr 5. link to original article contains dosing details in abstract PubMed
    2. Update: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. link to original article PubMed
14. 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 contains dosing details in manuscript PubMed NCT00644306
15. 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 contains dosing details in manuscript PubMed NCT00218855
16. 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 contains dosing details in manuscript PubMed ISRCTN90692740
17. 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 contains dosing details in abstract PubMed NCT00934154
18. 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 PubMed
19. 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 contains dosing details in manuscript PubMed NCT00405756

MP (Prednisolone)

MP: Melphalan & Prednisolone

Regimen variant #1, melphalan 0.25 mg/kg

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Keldsen et al. 1993	1987-1989	Phase 3 (C)	NOP	Seems to have superior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX)	2003-2007	Phase 3 (C)	CTDa	Not reported

Note: This is 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

1. 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 contains dosing details in abstract PubMed
2. 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 PubMed ISRCTN68454111
   1. 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 contains dosing details in manuscript link to PMC article PubMed
   2. 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 contains dosing details in manuscript PubMed
   3. 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 contains dosing details in manuscript link to PMC article PubMed
   4. Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article PubMed
3. 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sonneveld et al. 2012 (HOVON-65/GMMG-HD4)	2005-2008	Phase 3 (C)	PAD	Inferior 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.

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
• GMMG-HD4: Tandem autologous hematopoietic cell transplant

Regimen variant #2, 0.4/9/40 x 4 (CI doxorubicin, bolus vincristine, dex 12 days/cycle in cycles 1 & 2)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Harousseau et al. 2010 (IFM 2005-01)	2005-2008	Phase 3 (C)	VD	Might have inferior 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
  • Cycle 3 onwards: 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 consolidation versus high-dose melphalan with autologous hematopoietic cell transplant

Regimen variant #3, 0.4/9/40 (CI doxorubicin & vincristine, dex 4 days/cycle)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cook et al. 2004 (WOS MM1)	1996-2002	Phase 3 (C)	Z-Dex	Might have superior ORR
Attal et al. 2006 (IFM 99-02)	2000-2003	Non-randomized portion of 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, after 3 to 4 cycles

Regimen variant #4, 0.4/9/40 (CI doxorubicin & vincristine, dex 8 days/cycle)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Friedenberg et al. 2006 (ECOG E1A95)	1997-2000	Phase 3 (C)	VAD & Valspodar	Might have superior 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	Years 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	Years of enrollment	Evidence
Barlogie et al. 2006 (SWOG S9321)	1993-NR	Non-randomized portion of 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 cycles (see below)

Subsequent treatment

• SD or better: Randomized after 4 cycles to VBMCP versus melphalan & TBI, then auto HSCT

Regimen variant #7, 0.4/9/40 (Bolus doxorubicin, CI vincristine, dex 12 days per odd cycle)

Study	Years 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	Years of enrollment	Evidence
Samson et al. 1989	1984-1988	Non-randomized
Cavo et al. 2007 (Bologna 96)	1996-2001	Non-randomized portion of 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

Regimen variant #9, 2/50/40

Study	Years 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 with stem cell mobilization, then high dose melphalan with auto HSCT

References

1. 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 contains dosing details in manuscript PubMed
2. Segeren CM, Sonneveld P, van der Holt B, Baars JW, Biesma DH, Cornellissen JJ, Croockewit AJ, Dekker AW, Fibbe WE, Löwenberg B, van Marwijk Kooy M, van Oers MH, Richel DJ, Schouten HC, Vellenga E, Verhoef GE, Wijermans PW, Wittebol S, Lokhorst HM. Vincristine, doxorubicin and dexamethasone (VAD) administered as rapid intravenous infusion for first-line treatment in untreated multiple myeloma. Br J Haematol. 1999 Apr;105(1):127-30. link to original article contains dosing details in manuscript PubMed
3. Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol. 2003 Jul;14(7):1039-44. link to original article contains dosing details in abstract PubMed
4. Corso A, Barbarano L, Zappasodi P, Cairoli R, Alessandrino EP, Mangiacavalli S, Ferrari D, Fava S, Fiumanò M, Frigerio G, Isa L, Luraschi A, Klersy C, De Paoli A, Vergani C, Banfi L, Perego D, Ucci G, Pinotti G, Savarè M, Uziel L, Vismara A, Morra E, Lazzarino M. The VAD-DCEP sequence is an effective pre-transplant therapy in untreated multiple myeloma. Haematologica. 2004 Sep;89(9):1124-7. link to original article contains dosing details in manuscript PubMed
5. 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 PubMed NCT00006232
6. 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 PubMed
   1. 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 PubMed
   2. 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 PubMed
7. 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 contains dosing details in manuscript PubMed NCT00002878
8. 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 contains dosing details in manuscript PubMed NCT00344422
9. 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 contains dosing details in manuscript PubMed NCT00222053
   1. 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 PubMed
10. 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 contains dosing details in manuscript PubMed NCT00378222
    1. 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 contains dosing details in abstract PubMed
11. 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 PubMed NCT00002548
    1. 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 PubMed
12. 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 contains dosing details in manuscript PubMed NCT00028886
    1. 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 PubMed
13. 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 contains dosing details in abstract PubMed NCT00200681
14. HOVON-65/GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article contains dosing details in manuscript PubMed NTR213
    1. Subgroup analysis: Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. link to original article PubMed
    2. 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 PubMed
15. 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 PubMed NCT02288741

VAMP

VAMP: Vincristine, Adriamycin (Doxorubicin), MethylPrednisolone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gore et al. 1989	1985-1988	Phase 2
Raje et al. 1997	1985-1994	Non-randomized
Fermand et al. 1998	1990-1995	Phase 3 (E-switch-ic)	VMCP	Seems to have superior EFS
Fermand et al. 2005	1991-1998	Phase 3 (E-switch-ic)	VMCP	Might have superior EFS

Note: this is to be distinguished from the VAMP protocols used in AML and Hodgkin lymphoma.

Chemotherapy

• Vincristine (Oncovin)
• Doxorubicin (Adriamycin)

Glucocorticoid therapy

• Methylprednisolone (Solumedrol)

Subsequent treatment

• Raje et al. 1997: HDT with autograft (details not specified in abstract)
• Fermand et al. 1998: Lomustine, melphalan, TBI with auto HSCT
• Fermand et al. 2005: MEL200 with auto HSCT or melphalan & busulfan with auto HSCT

References

1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed

VBMC

VBMC: Vincristine, BiCNU (Carmustine), Melphalan, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Child et al. 2003 (MRC Myeloma VII)	1993-2000	Phase 3 (C)	Melphalan & Methylprednisolone, then auto HSCT	Seems to have inferior OS

Chemotherapy

• Vincristine (Oncovin)
• Carmustine (BCNU)
• Melphalan (Alkeran)
• Cyclophosphamide (Cytoxan)

Subsequent treatment

• Interferon alfa maintenance

References

1. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article PubMed

VBMCP

VBMCP: Vincristine, BiCNU (Carmustine), Melphalan, Cyclophosphamide, Prednisone
VBCMP: Vincristine, BiCNU (Carmustine), Cyclophosphamide, Melphalan, Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Oken et al. 1997 (ECOG E2479)	1979-1983	Phase 3 (E-esc-ic)	MP	Superior ORR
Oken et al. 1999 (ECOG E9486)	1988-1992	Phase 3 (C)	1. VBMCP/HiCy	Did not meet primary endpoint of OS
			2. VBMCP/IFN	Seems to have inferior TTP
Barlogie et al. 2006 (SWOG S9321)	1993-NR	Phase 3 (C)	Melphalan & TBI, then auto HSCT	Did not meet primary endpoints of ORR/OS
Kyle et al. 2009 (ECOG E5A93)	1994-2002	Phase 3 (C)	VBMCP/HiCy & IFN	Did not meet primary endpoint of OS

Chemotherapy

• Vincristine (Oncovin)
• Carmustine (BCNU)
• Melphalan (Alkeran)
• Cyclophosphamide (Cytoxan)

Glucocorticoid therapy

• Prednisone (Sterapred)

References

1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed NCT00002548
   1. 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 PubMed
5. 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 PubMed NCT00002556

VBMCP/VBAD

VBMCP/VBAD: Vincristine, BiCNU (Carmustine), Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, BiCNU (Carmustine), Adriamycin (Doxorubicin), Dexamethasone

Protocol

Study	Years of enrollment	Evidence
Bladé et al. 2005	1994-1999	Non-randomized portion of RCT
Rosiñol et al. 2008 (PETHEMA MM 2000)	1999-2004	Non-randomized portion of RCT

Chemotherapy, VBMCP portion

• Vincristine (Oncovin)
• Carmustine (BCNU)
• Melphalan (Alkeran)
• Cyclophosphamide (Cytoxan)

Glucocorticoid therapy, VBMCP portion

• Prednisone (Sterapred)

Chemotherapy, VBAD portion

• Vincristine (Oncovin)
• Carmustine (BCNU)
• Doxorubicin (Adriamycin)

Glucocorticoid therapy, VBAD portion

• Dexamethasone (Decadron)

Subsequent treatment

• Bladé et al. 2005, with response after 4 cycles: VBMCP/VBAD x 8 (12 cycles total) versus HDT with MEL200 with auto HSCT or MEL140 & TBI with auto HSCT
• PETHEMA MM 2000: Bu/Mel with tandem auto HSCT versus Bu/Mel with auto HSCT, then RIC allo HSCT

References

1. 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 PubMed
2. 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 PubMed NCT00560053

VMCP

VMCP: Vincristine, Melphalan, Cyclophosphamide, Prednisone
VCMP: Vincristine, Cyclophosphamide, Melphalan, Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Alexanian et al. 1977 (SWOG S7305)	1973-1974	Phase 3 (E-esc-ic)	Alkylator-prednisone combinations	Superior OS
Fermand et al. 2005	1991-1998	Phase 3 (C)	VAMP, then auto HSCT	Might have inferior 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

1. 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 PubMed
2. 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 articlecontains dosing details in manuscript PubMed

VMCP/VBAP

VMCP/VBAP: Vincristine, Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, BiCNU (Carmustine), Adriamycin (Doxorubicin), Prednisone

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Durie et al. 1986 (SWOG S7927/S7928)	1979-1982	Phase 3 (E-esc-ic)	VCP	Seems to have superior OS
Salmon et al. 1990 (SWOG S8229/S8230)	1982-1987	Non-randomized portion of RCT
Attal et al. 1996 (IFM90)	1990-1993	Non-randomized portion of RCT

Chemotherapy, VMCP portion

• 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

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

21-day cycle for 2 to 3 cycles, alternating with VBAP

Chemotherapy, VBAP portion

• 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

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 4

21-day cycle for 2 to 3 cycles, alternating with VMCP VMCP and VBAP are given in an alternating fashion for a total of 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 versus VMCP/VBAP x 18 total cycles

References

1. 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 PubMed
2. 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 PubMed
3. 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 contains dosing details in manuscript PubMed

VMCP/VCAP

VMCP/VCAP: Vincristine, Melphalan, Cyclophosphamide, Prednisone alternating with Vincristine, Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Salmon et al. 1983 (SWOG S7704)	1977-1979	Phase 3 (E-esc-ic)	MP	Superior OS

Chemotherapy, VMCP portion

• Vincristine (Oncovin)
• Melphalan (Alkeran)
• Cyclophosphamide (Cytoxan)

Glucocorticoid therapy, VMCP portion

• Prednisone (Sterapred)

Chemotherapy, VCAP portion

• Vincristine (Oncovin)
• Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin)

Glucocorticoid therapy, VCAP portion

• Prednisone (Sterapred)

References

1. 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 PubMed

Consolidation after first-line therapy

Melphalan monotherapy

Regimen

Study	Years of enrollment	Evidence
McElwain & Powles 1983	NR	Pilot Study
Segeren et al. 2003 (HOVON 24)	1995-2000	Non-randomized portion 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: 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, then interferon maintenance versus interferon maintenance

References

1. McElwain TJ, Powles RL. High-dose intravenous melphalan for plasma-cell leukaemia and myeloma. Lancet. 1983 Oct 8;2(8354):822-4. link to original article PubMed
2. 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 PubMed
   1. 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 PubMed

Melphalan, then auto HSCT, then Melphalan & Busulfan, then auto HSCT

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cavo et al. 2007 (Bologna 96)	1996-2001	Phase 3 (E-esc-ic)	Melphalan, then auto HSCT	Superior EFS Median EFS: 35 vs 23 mo

Chemotherapy, first transplant

• Melphalan (Alkeran) 200 mg/m² IV once on day -2

Stem cells re-infused on day 0

Chemotherapy, second transplant

• Melphalan (Alkeran) 120 mg/m² IV once on day -4
• Busulfan (Myleran) 4 mg/kg PO from day -5 to -3

Stem cells re-infused on day 0

References

1. Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. J Clin Oncol. 2007 Jun 10;25(17):2434-41. Epub 2007 May 7. link to original article contains dosing details in manuscript PubMed

MEL200, then auto HSCT, then MEL220 & Dexamethasone, then auto HSCT

Protocol

Study	Years 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 regimen was meant for patients who did not have an HLA-identical sibling donor.

Preceding treatment

• VAD induction x 4

Chemotherapy, first transplant

• Melphalan (Alkeran) 200 mg/m² IV once on day -2

Stem cells re-infused on day 0

Chemotherapy, second transplant

• 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)

Stem cells re-infused on day 0 No further treatment.

References

1. 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 contains dosing details in manuscript PubMed
   1. 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 contains dosing details in manuscript PubMed
   2. 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 PubMed
   3. 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 PubMed

Melphalan, then auto HSCT, then Melphalan & TBI, then auto HSCT

Protocol variant #1, lower radiation

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Attal et al. 2003 (IFM94)	1994-1997	Phase 3 (E-esc-ic)	MEL140-TBI & auto HSCT	Superior OS OS84: 42% vs 21%

Preceding treatment

• VAD x 3 to 4

Chemotherapy, first transplant

• Melphalan (Alkeran) 100 mg/m² IV once per day on days -3 & -2

Stem cells re-infused on day 0

Chemotherapy, second transplant

• Melphalan (Alkeran) 140 mg/m² IV once on day -4

Radiotherapy

• Total body irradiation (TBI) in 2 Gy fractions once per day x 4 = total dose of 8 Gy, without lung shielding

Stem cells re-infused on day 0

Subsequent treatment

• Interferon alfa maintenance

Protocol variant #2, higher radiation

Study	Years 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, first transplant

• Melphalan (Alkeran) 100 mg/m² IV once per day on days -3 & -2

Stem cells re-infused on day 0

Chemotherapy, second transplant

• Melphalan (Alkeran) 140 mg/m² IV once on day -4

Radiotherapy

• Total body irradiation (TBI): 850 to 1020 cGy in 5 to 6 fractions delivered on days -3 to -1

Stem cells re-infused on day 0

References

1. 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 PubMed
   1. 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 contains dosing details in manuscript PubMed
   2. 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 PubMed
2. 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 contains dosing details in manuscript PubMed
   1. 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 PubMed

Melphalan, then auto HSCT, then Fludarabine, Busulfan, ATG, then allo HSCT

Protocol

Study	Years of enrollment	Evidence
Garban et al. 2006 (IFM99-03)	2000-2004	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

Chemotherapy

• Fludarabine (Fludara) 25 mg/m²/day (route not specified) for 5 days (days not specified)
• Busulfan (Myleran) 2 mg/kg PO once per day for 2 days (days not specified)

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• ATG, rabbit (Imtix) 2.5 mg/kg IV over 12 hours once per day on days -5 to -1
• Cyclosporine 3 mg/kg/day (route not specified), starting on day -1
• Methotrexate (MTX) 10 mg/m² (route not specified) once per day on days +1, +3, +6

One course

Dose and schedule modifications

• Cyclosporine doses adjusted to "serum levels", tapered on day +60 to off by day +100 (if no GVHD)

Immunotherapy

• Allogeneic stem cells

Stem cells re-infused on day 0

References

1. 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 contains dosing details in manuscript PubMed
   1. 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 PubMed
   2. 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 PubMed

Melphalan, then auto HSCT, then TBI, then allo HSCT

Protocol

Study	Years of enrollment	Evidence
Bruno et al. 2007	1998-2004	Non-randomized

Note: This regimen was meant for patients who had an HLA-identical sibling donor.

Preceding treatment

• VAD induction

Chemotherapy, auto HSCT

• Melphalan (Alkeran) 200 mg/m² IV once on day -2

Stem cells re-infused on day 0, followed by:

Radiotherapy, allo HSCT

• TBI 2 Gy

Immunotherapy

• Allogeneic stem cells

Stem cells re-infused on day 0

References

1. 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 PubMed NCT00415987

Melphalan & Methylprednisolone, then auto HSCT

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Child et al. 2003 (MRC Myeloma VII)	1993-2000	Phase 3 (E-esc-ic)	VBMC	Seems to have superior OS Median OS: 54.1 vs 42.3 mo

Preceding treatment

• VAMP induction

Chemotherapy

• Melphalan (Alkeran)

Glucocorticoid therapy

• Methylprednisolone (Solumedrol)

Subsequent treatment

• Interferon alfa maintenance

References

1. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003 May 8;348(19):1875-83. link to original article PubMed

Melphalan & TBI, then auto HSCT

Regimen variant #1, MEL140 & TBI 8 Gy

Study	Years 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 superior OS
Barlogie et al. 2006 (SWOG S9321)	1993-NR	Phase 3 (E-esc-ic)	VBMCP	Did not meet 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	Inferior OS
Moreau et al. 2002 (IFM 9502)	1995-1999	Phase 3 (C)	High-dose melphalan & autologous transplant	Might have inferior OS

Preceding treatment

• IFM90: VMCP alternating with VBAP x 4 to 6 cycles
• IFM 9502 and SWOG S9321: VAD x 3
• IFM 94: VAD x 3 to 4

Chemotherapy

• Melphalan (Alkeran) 140 mg/m² IV (day not specified)

Radiotherapy

• Total body irradiation (TBI) in 2 Gy fractions once per day x 4 = total dose of 8 Gy, without lung shielding

One course; relative date of stem cell re-infusion not specified

Subsequent treatment

• Interferon alfa maintenance

Regimen variant #2, MEL140 & TBI 12 Gy

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bladé et al. 2005	1994-1999	Phase 3 (E-esc-ooc)	1. MEL200 with auto HSCT 2. 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 inferior CR, there was no difference in PFS or OS.

Preceding treatment

• VBMCP/VBAD x 4

Chemotherapy

• Melphalan (Alkeran) 140 mg/m² IV once on day -2

Radiotherapy

• Total body irradiation (TBI) in 3 Gy fractions once per day on days -6 to -3 = total dose of 12 Gy

Re-infusion of stem cells on day 0

Subsequent treatment

• IFN & Dex maintenance

References

1. 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 contains dosing details in manuscript PubMed
   1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
   1. 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 PubMed
4. 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 dosing details in manuscript PubMed
5. 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 PubMed NCT00002548
   1. 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 PubMed

Maintenance after first-line therapy

Dexamethasone monotherapy

Regimen variant #1, 1 year

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Maiolino et al. 2012 (GBRAM0001)	2003-2008	Phase 3 (C)	Thal-Dex	Inferior PFS

Preceding treatment

• High-dose melphalan with autologous hematopoietic stem cell transplant

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	Years of enrollment	Evidence
Cavo et al. 2010 (GIMEMA MM-BO2005)	2006-2008	Non-randomized portion of 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

1. 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 contains dosing details in abstract PubMed NCT01134484
   1. Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article contains dosing details in manuscript PubMed
2. 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 contains dosing details in manuscript PubMed NCT01296503

Interferon alfa monotherapy

Regimen

Study	Years 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

Immunotherapy

• Interferon alfa

References

1. 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 PubMed
   1. 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 PubMed
2. Meta-analysis: Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol. 2000 Nov;11(11):1427-36. link to original article PubMed
3. 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 contains dosing details in manuscript PubMed NCT00028886
   1. 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 PubMed

Interferon alfa-2a monotherapy

Regimen

Study	Years of enrollment	Evidence
Child et al. 2003 (MRC Myeloma VII)	1993-2000	Non-randomized portion of phase 3 RCT

Immunotherapy

• Interferon alfa-2a (Roferon-A)

References

1. 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 PubMed NCT00002599

Interferon alfa-2b monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Mandelli et al. 1990	1985-1988	Phase 3 (E-esc)	Observation	Might have superior OS
Browman et al. 1995	1987-1992	Phase 3 (E-esc)	Observation	Seems to have superior OS
Schaar et al. 2005 (HOVON-16)	1991-1997	Phase 3 (E-esc)	Observation	Superior PFS
Ludwig et al. 2008 (01-002-0601)	2001-2007	Phase 3 (C)	Interferon alfa-2b & Thalidomide	Inferior PFS
Rosiñol et al. 2012 (GEM05/MENOS65)	2006-2009	Phase 3 (C)	1. Thalidomide	Not reported
			2. VT	Seems to have inferior PFS1

¹Reported efficacy for GEM05/MENOS65 is based on the 2017 update.

Preceding treatment

• Mandelli et al. 1990: MP x 12 mo or VMCP/VBAP x 12 mo
• HOVON-16: MP

Immunotherapy

• Interferon alfa-2b (Intron-A)

References

1. 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 PubMed
2. 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 PubMed
3. 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 PubMed
4. 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 PubMed
5. 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 PubMed NCT00205751
   1. 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 PubMed
6. 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 contains dosing details in manuscript PubMed NCT00461747
   1. 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 contains dosing details in manuscript PubMed

Interferon alfa & Dexamethasone

Regimen

Study	Years of enrollment	Evidence
Bladé et al. 2005	1994-1999	Non-randomized portion of RCT

Note: this study did not specify an exact type of interferon alfa.

Preceding treatment

• VBMCP/VBAD x 4, then HDT with MEL200 with auto HSCT or MEL140 & TBI with auto HSCT versus VBMCP/VBAD x 12

Immunotherapy

• Inteferon alfa

Glucocorticoid therapy

• Dexamethasone (Decadron)

References

1. 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 PubMed

Interferon alfa-2b & Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Salmon et al. 1998 (SWOG 9028)	1990-1993	Phase 3 (E-esc-ooc)	Interferon alfa-2b	Superior PFS

Immunotherapy

• Interferon alfa-2b (Intron-A)

Glucocorticoid therapy

• Prednisone (Sterapred)

References

1. 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 PubMed

Interferon alfa-2b & Thalidomide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ludwig et al. 2008 (01-002-0601)	2001-2007	Phase 3 (E-esc-ooc)	Interferon alfa-2b	Superior PFS

Immunotherapy

• Interferon alfa-2b (Intron-A)

Targeted therapy

• Thalidomide (Thalomid)

References

1. 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 PubMed NCT00205751
   1. 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 PubMed

Prednisolone monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Spencer et al. 2009 (ALLG MM6)	2002-2005	Phase 3 (C)	Thalidomide & Prednisolone	Inferior OS

Preceding treatment

• High-dose melphalan & auto HSCT

Glucocorticoid therapy

• Prednisolone (Millipred) 50 mg PO once every other day

Continued indefinitely

References

1. 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 contains dosing details in manuscript PubMed ACTRN12607000382471
   1. 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 PubMed
   2. 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 PubMed

Prednisone monotherapy

Regimen variant #1, high-dose

Study	Years 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 superior OS

Preceding treatment

• VAD-P versus VAD-P/Q

Glucocorticoid therapy

• Prednisone (Sterapred) 50 mg PO once every other day

Continued indefinitely

Regimen variant #2, low-dose

Study	Years 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 inferior OS

Preceding treatment

• VAD-P versus VAD-P/Q

Glucocorticoid therapy

• Prednisone (Sterapred) 10 mg PO once every other day

Continued indefinitely

References

1. Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. link to original article contains dosing details in abstract PubMed

Relapsed or refractory

Bortezomib monotherapy

Regimen variant #1, 1 mg/m², 21-day cycle x 8

Study	Years 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-NR	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 escalation to bortezomib & dexamethasone

Regimen variant #2, 1.3 mg/m², 21-day cycle x 8 (IV)

Study	Years 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)	2002-2003	Phase 3 (E-RT-switch-ooc)	High-dose dexamethasone	Seems to have superior OS1 (HR 0.77)
Petrucci et al. 2013 (RETRIEVE)	2006-NR	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

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 escalation to bortezomib & dexamethasone
• APEX: Bortezomib consolidation
• MMY-3021, patients with suboptimal response after 4 cycles: Optional escalation to bortezomib & dexamethasone
• MMY-3021, patients who were "evolving" towards CR after 8 cycles: Optional 2 additional cycles (10 total)

Regimen variant #3, 1.3 mg/m², 21-day cycle x 8 (SC)

Study	Years 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

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

• Patients with suboptimal response after 4 cycles could escalate to bortezomib & dexamethasone; 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	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2003 (SUMMIT)	2001	Phase 2 (RT)
Orlowski et al. 2007 (MMY-3001)	2004-2006	Phase 3 (C)	Bortezomib & PLD	Inferior TTP
Dimopoulos et al. 2013 (VANTAGE 088)	2008-2011	Phase 3 (C)	Bortezomib & Vorinostat	Inferior PFS

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 escalation to bortezomib & dexamethasone

Regimen variant #6, 1.6 mg/m², 35-day cycle x 10

Study	Years 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

1. 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 contains dosing details in manuscript PubMed
   1. Subgroup analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains dosing details in abstract PubMed
   2. 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 PubMed
2. 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 contains dosing details in manuscript PubMed
   1. Subgroup Analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article contains dosing details in abstract PubMed
   2. Update: Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. link to original article PubMed
3. 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 contains dosing details in manuscript PubMed NCT00048230
   1. 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 PubMed
   2. 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 contains dosing details in manuscript PubMed
4. 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 contains dosing details in manuscript PubMed NCT00103506
   1. 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 contains dosing details in manuscript PubMed
   2. 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 PubMed
5. Hainsworth JD, Spigel DR, Barton J, Farley C, Schreeder M, Hon J, Greco FA. Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network. Cancer. 2008 Aug 15;113(4):765-71. link to original article contains dosing details in manuscript PubMed
6. 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 contains dosing details in manuscript PubMed NCT00722566
   1. 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 PubMed
   2. 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 PubMed
7. 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 contains dosing details in abstract PubMed NCT00473590
8. 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 contains dosing details in manuscript PubMed NCT00431769
9. 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 contains dosing details in manuscript PubMed NCT00773747
10. 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 contains dosing details in manuscript link to PMC article PubMed NCT00401843

Carmustine & Doxorubicin

Regimen

Study	Years of enrollment	Evidence
Alberts et al. 1976	1974-1975	Non-randomized, <20 pts

Chemotherapy

• Carmustine (BCNU)
• Doxorubicin (Adriamycin)

References

1. 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 PubMed

Dexamethasone monotherapy

Regimen variant #1, indefinite, high-dose

Study	Years 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)	2011-2012	Phase 3 (C)	PD	Inferior 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, 9 to 12, 17 to 20

28-day cycles

Regimen variant #2, indefinite, weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Spicka et al. 2019 (ADMYRE)	2010-2015	Phase 3 (C)	Plitidepsin & Dexamethasone	Inferior 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 per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #3, indefinite, with de-escalation

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2007 (MM-009)	2003-2004	Phase 3 (C)	RD	Seems to have inferior OS1
Dimopoulos et al. 2007 (MM-010)	2003-2004	Phase 3 (C)	RD	Seems to have inferior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2005 (APEX)	2002-2003	Phase 3 (C)	Bortezomib	Seems to have inferior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kropff et al. 2011 (OPTIMUM)	2006-2009	Phase 3 (C)	1. Thalidomide; 100 mg/d 2. 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

1. 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 contains dosing details in manuscript PubMed NCT00048230
   1. 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 PubMed
   2. Update: Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. link to original article PubMed
2. 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 contains dosing details in manuscript PubMed NCT00424047
   1. 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 PubMed
3. 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 contains dosing details in manuscript PubMed NCT00056160
   1. 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 PubMed
4. 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 PubMed NCT00017602
5. 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 contains dosing details in manuscript PubMed NCT00452569
6. 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 contains dosing details in manuscript PubMed NCT01311687
   1. 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 PubMed
7. 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 contains dosing details in abstract PubMed NCT01102426

EDAP

EDAP: Etoposide, Dexamethasone, Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study	Years of enrollment	Evidence
Barlogie et al. 1989	NR	Non-randomized

Chemotherapy

• Etoposide (Vepesid)
• Cytarabine (Ara-C)
• Cisplatin (Platinol)

Glucocorticoid therapy

• Dexamethasone (Decadron)

References

1. 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 PubMed

Melphalan flufenamide & Dexamethasone

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2020 (HORIZONRRMM)	2016-2019	Phase 2 (RT)
Schjesvold et al. 2022 (OCEAN)	2017-2020	Phase 3 (E-switch-ooc)	PD	Seems to have superior PFS Median PFS: 6.8 vs 4.9 mo (HR 0.79, 95% CI 0.64-0.98)

Note: this variant is intended for patients 75 or younger. HORIZON should not be confused with the trial by the same name in breast cancer.

Peptide-drug conjugate therapy

• Melphalan flufenamide (Pepaxto) 40 mg IV over 30 minutes once on day 1

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2020 (HORIZONRRMM)	2016-2019	Phase 2 (RT)
Schjesvold et al. 2022 (OCEAN)	2017-2020	Phase 3 (E-switch-ooc)	PD	Seems to have superior PFS Median PFS: 6.8 vs 4.9 mo (HR 0.79, 95% CI 0.64-0.98)

Note: this variant is intended for patients older than 75. HORIZON should not be confused with the trial by the same name in breast cancer.

Peptide-drug conjugate therapy

• Melphalan flufenamide (Pepaxto) 40 mg IV over 30 minutes once on day 1

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22

28-day cycles

References

1. HORIZON: Richardson PG, Oriol A, Larocca A, Bladé J, Cavo M, Rodriguez-Otero P, Leleu X, Nadeem O, Hiemenz JW, Hassoun H, Touzeau C, Alegre A, Paner A, Maisel C, Mazumder A, Raptis A, Moreb JS, Anderson KC, Laubach JP, Thuresson S, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Mateos MV; HORIZON (OP-106) Investigators. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. J Clin Oncol. 2021 Mar 1;39(7):757-767. Epub 2020 Dec 9. link to original article contains dosing details in abstract PubMed NCT02963493
2. OCEAN: Schjesvold FH, Dimopoulos MA, Delimpasi S, Robak P, Coriu D, Legiec W, Pour L, Špička I, Masszi T, Doronin V, Minarik J, Salogub G, Alekseeva Y, Lazzaro A, Maisnar V, Mikala G, Rosiñol L, Liberati AM, Symeonidis A, Moody V, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Hájek R, Mateos MV, Richardson PG, Sonneveld P; OCEAN (OP-103) Investigators. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study. Lancet Haematol. 2022 Feb;9(2):e98-e110. Epub 2022 Jan 12. link to original article contains dosing details in manuscript PubMed NCT03151811

Pomalidomide, Dexamethasone, Pembrolizumab

Regimen

Study	Years 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)

Glucocorticoid therapy

• Dexamethasone (Decadron)

Immunotherapy

• Pembrolizumab (Keytruda)

References

1. 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 PubMed NCT02289222

Stilbamidine & Urethane

Regimen

Study	Evidence
Alwall 1947	Case series

Purely of historic interest.

Chemotherapy

• Stilbamidine
• Urethane

References

1. 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 PubMed

Tisagenlecleucel monotherapy

Regimen

Study	Evidence
Garfall et al. 2015 (UPCC02413)	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

1. 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 PubMed NCT02135406

Urethane monotherapy

Regimen

Study	Years 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 inferior OS

References

1. 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 PubMed
2. 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 PubMed

VAD

VAD: Vincristine, Adriamycin (Doxorubicin), Dexamethasone
VAd: Vincristine, Adriamycin (Doxorubicin), low-dose dexamethasone

Regimen

Study	Years 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

1. Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med. 1984 May 24;310(21):1353-6. link to original article contains dosing details in manuscript PubMed
2. 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 PubMed

VAD & Cyclosporine

VAD & Cyclosporine: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Cyclosporine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sonneveld et al. 1992	NR	Non-randomized
Sonneveld et al. 2001 (EORTC 06914)	NR	Phase 2/3 (E-esc-ooc)	VAD	Did not meet primary endpoint of best RR

Chemotherapy

• Vincristine (Oncovin)
• Doxorubicin (Adriamycin)

Glucocorticoid therapy

• Dexamethasone (Decadron)

Immunosuppressive therapy

• Cyclosporine

References

1. 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 PubMed
2. 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 PubMed