Multiple myeloma, induction

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Note: due to its size/complexity, multiple myeloma has been split into sub-pages. This page covers induction regimens for both transplant eligible and ineligible patients. As this distinction can often be unclear, we do not separate regimens on this basis. Rather, the page is organized by doublets, triplets, quadruplets, and other combinations. The top-line inclusion criteria from each prospectively enrolling regimen are reported.
*Induction (transplant eligible and ineligible) [this page]
*First-line consolidation and maintenance
*Relapsed/refractory, including subsequent consolidation and maintenance
*Smoldering multiple myeloma
Last updated on 2024-09-06:48 regimens on this page
118 variants on this page
=Guidelines=
Please go to the general multiple myeloma page for a list of clinical practice guidelines.
=First-line therapy, doublets=
==Bortezomib & Dexamethasone (Vd)==
Vd: Velcade (Bortezomib), low-dose dexamethasone
Bd: Bortezomib, low-dose dexamethasone
Bort-Dex: Bortezomib, Dexamethasone
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Niesvizky et al. 2015 (UPFRONT)	2007-2010 	Phase 3b (E-de-esc)	1. VMP 	Did not meet primary endpoint of PFS
Niesvizky et al. 2015 (UPFRONT)	2007-2010 	Phase 3b (E-de-esc)	2. VTD 	Did not meet primary endpoint of PFS
Note: This regimen was meant for transplant ineligible patients.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
**Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5
21-day cycle for 8 cycles
====Subsequent treatment====
*Bortezomib consolidation
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Moreau et al. 2011 (IFM 2007-02)	2008-03 to 2009-01 	Phase 3 (C)	vtD 	Lower VGPR rate
Note: This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
**Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4
21-day cycle for 4 cycles
====Subsequent treatment====
*High-dose melphalan, then autologous hematopoietic cell transplant consolidation
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Harousseau et al. 2010 (IFM 2005-01)	2005-2008 	Phase 3 (E-switch-ooc)	VAD 	Might have longer PFS (secondary endpoint)Median PFS: 36 vs 29.7 mo(HR not reported, p=0.064)Higher post-induction CR/nCR rate (composite primary outcome)CR/nCR rate: 14.8% vs 6.4%
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 g/dL) or urine (greater than 0.2 g/24 h).
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12 
**Cycles 3 & 4: 40 mg PO once per day on days 1 to 4
====Supportive therapy====
*One of the following bisphosphonates recommended:
**Pamidronate (Aredia) 90 mg IV once every 4 weeks until first transplant
**Zoledronic acid (Zometa) 4 mg IV once every 4 weeks until first transplant
*"Antibiotics, antifungal agents, and antiviral prophylaxis in accordance with local practice."
21-day cycle for 4 cycles
====Subsequent treatment====
*DCEP versus high-dose melphalan with autologous hematopoietic cell transplant consolidation
===Regimen variant #4, weekly bortezomib===
Study 	Dates of enrollment 	Evidence
Girnius et al. 2014 (X05153)	2007 to not reported	Phase 2
====Targeted therapy====
*Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
35-day cycle for up to 6 cycles
===References===
# IFM 2005-01: Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010 Oct 20;28(30):4621-9. Epub 2010 Sep 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00200681
## Subgroup analysis: Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guérin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L, Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S, Harousseau JL. Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010 Oct 20;28(30):4630-4. Epub 2010 Jul 19. link to original article EuroPMC
# IFM 2007-02: Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00910897
# X05153: Girnius SK, Lee S, Kambhampati S, Rose MG, Mohiuddin A, Houranieh A, Zimelman A, Grady T, Mehta P, Behler C, Hayes TG, Efebera YA, Prabhala RH, Han A, Yellapragada SV, Klein CE, Roodman GD, Lichtenstein A, Munshi NC. A phase II trial of weekly bortezomib and dexamethasone in veterans with newly diagnosed multiple myeloma not eligible for or who deferred autologous stem cell transplantation. Br J Haematol. 2015 Apr;169(1):36-43. Epub 2015 Jan 8. Epub 2014 Sep 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01090921
# UPFRONT: Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00507416
==Bortezomib & Prednisone (VP)==
VP: Velcade (Bortezomib) & Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence
Larocca et al. 2016 (MMY2069)	2010-10 to 2012-08 	Phase 2
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Prednisone (Sterapred) 50 mg PO once every other day
28-day cycle for 9 cycles
====Subsequent treatment====
*Bortezomib maintenance
===References===
# MMY2069: Larocca A, Bringhen S, Petrucci MT, Oliva S, Falcone AP, Caravita T, Villani O, Benevolo G, Liberati AM, Morabito F, Montefusco V, Passera R, De Rosa L, Omedé P, Vincelli ID, Spada S, Carella AM, Ponticelli E, Derudas D, Genuardi M, Guglielmelli T, Nozzoli C, Aghemo E, De Paoli L, Conticello C, Musolino C, Offidani M, Boccadoro M, Sonneveld P, Palumbo A. A phase 2 study of three low-dose intensity subcutaneous bortezomib regimens in elderly frail patients with untreated multiple myeloma. Leukemia. 2016 Jun;30(6):1320-6. Epub 2016 Feb 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01190787
==Lenalidomide & Dexamethasone (Rd)==
Rd: Revlimid (Lenalidomide) & low-dose dexamethasone
RevDex: Revlimid (Lenalidomide) & Dexamethasone
Ld: Lenalidomide & low-dose dexamethasone
LenDex: Lenalidomide & Dexamethasone
===Regimen variant #1, limited duration (4 cycles)===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rajkumar et al. 2009 (ECOG E4A03)	2004-2006 	Phase 3 (E-de-esc) 	RD 	Longer OS (secondary endpoint)OS24: 87% vs 75%(aHR 0.40, 95% CI 0.23-0.70)Inconclusive whether non-inferior RR after 4 cycles (primary endpoint)
Gay et al. 2010 	2004-2008 	Retrospective 	 	
Palumbo et al. 2014 (MPRvsMEL200)	2007-2009 	Non-randomized part of phase 3 RCT	 	
Gay et al. 2015 (EMN-441) 	2009-2011 	Non-randomized part of phase 3 RCT	 	
Note: In ECOG E4A03 this is the low-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. MPRvsMEL200 was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were 65 years of age or younger. EMN-441 was intended for transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger.
====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, 8, 15, 22
====Supportive therapy====
(as described in Rajkumar et al. 2009):
*One of the following bisphosphonates:
**Pamidronate (Aredia) 90 mg IV over 2 to 4 hours once every 4 weeks
**Zoledronic acid (Zometa) 4 mg IV over 15 minutes once every 4 weeks
*Thromboprophylaxis mandatory (added mid-protocol after excess rates of DVT)
28-day cycle for 4 cycles
====Subsequent treatment====
*ECOG E4A03: Responding patients could choose after 4 cycles to proceed to high-dose melphalan with autologous hematopoietic cell transplant or to continue Rd indefinitely
*ECOG E4A03, non-responders: Second-line Thal-Dex (details not described)
*MPRvsMEL200: Tandem high-dose melphalan with autologous hematopoietic cell transplant versus MPR consolidation
*EMN-441: Tandem high-dose melphalan with autologous hematopoietic cell transplant versus CRd consolidation
===Regimen variant #2, limited duration (6 cycles)===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Durie et al. 2016 (SWOG S0777)	2008-2012 	Phase 3 (C)	VRd 	Shorter PFS (primary endpoint)Median PFS: 30 vs 43 mo(HR 1.41, 96% CI 1.10-1.79)Shorter OS1 (secondary endpoint)Median OS: 69 vs NYR mo(HR 1.41, 96% CI 1.08-1.85)
1Reported efficacy is based on the 2020 update.
====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, 8, 15, 22
28-day cycle for 6 cycles
====Subsequent treatment====
*Rd maintenance
===Regimen variant #3, limited duration (9 cycles)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Magarotto et al. 2016 (EMN01) 	2009-2012 	Phase 3 (E-de-esc)	1. CPR 	Did not meet primary endpoint of PFS
Magarotto et al. 2016 (EMN01) 	2009-2012 	Phase 3 (E-de-esc)	2. MPR 	Might have shorter PFS
Larocca et al. 2021 (RV-MM-PI-0752)	2014-2017 	Phase 3 (E-de-esc)	Rd; continuous	Seems to have longer EFS (primary endpoint)Median EFS: 10.4 vs 6.9 mo(HR 0.70, 95% CI 0.51-0.95)
Note: In EMNO1, this regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. In RV-MM-PI-0752, this regimen is intended for patients between 65 and 80 years of age who were ineligible for transplant.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following study-specific criteria:
**EMN01, age 65 to 75 years: 40 mg PO once per day on days 1, 8, 15, 22
**EMN01, age greater than 75 years & RV-MM-PI-0752, all patients: 20 mg PO once per day on days 1, 8, 15, 22
====Supportive therapy====
*One of the following was mandatory:
**Aspirin or 
**LMWH or 
**Warfarin (Coumadin)
28-day cycle for 9 cycles
====Subsequent treatment====
*EMN01: Lenalidomide versus RP maintenance
*RV-MM-PI-0752: Lenalidomide maintenance
===Regimen variant #4, limited duration (18 cycles, "Rd18")===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Benboubker et al. 2014 (FIRSTMM)	2008-2011 	Phase 3 (E-RT-switch-ooc)	1. MPT 	Longer OS1 (secondary endpoint)Median OS: 62 vs 49 mo(HR not reported)
Benboubker et al. 2014 (FIRSTMM)	2008-2011 	Phase 3 (E-RT-switch-ooc)	2. Rd; continuous	Did not meet primary endpoint of PFS1
1Reported efficacy is based on the 2017 update.
Note: This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose.
====Targeted therapy====
*Lenalidomide (Revlimid) by the following renal function-based criteria:
**CrCl more than 50 mL/min/1.73m2: 25 mg PO once per day on days 1 to 21
**CrCl 30 to 50 mL/min/1.73m2: 10 mg PO once per day on days 1 to 21
**CrCl less than 30 mL/min/1.73m2: 15 mg PO once every other day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**75 years old or younger: 40 mg PO once per day on days 1, 8, 15, 22
**Older than 75 years old: 20 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 18 cycles
===Regimen variant #5, indefinite 28-day cycles===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Benboubker et al. 2014 (FIRSTMM) 	2008-2011 	Phase 3 (E-RT-switch-ooc)	1. MPT 	Longer PFS (primary endpoint)Median PFS: 25.5 vs 21.2 mo(HR 0.72, 95% CI 0.61-0.85)Longer OS1 (secondary endpoint)Median OS: 59 vs 49 mo(HR 0.78, 95% CI 0.67-0.92)
Benboubker et al. 2014 (FIRSTMM) 	2008-2011 	Phase 3 (E-RT-switch-ooc)	2. Rd; Rd18 	Did not meet primary endpoint of PFS1
Dimopoulos et al. 2022 (ELOQUENT-1)	2011-2014 	Phase 3 (C) 	Elo-Rd 	Did not meet primary endpoint of PFSMedian PFS: 29.5 vs 31.4 mo(HR 1.08, 95% CI 0.89-1.30)
Facon et al. 2019 (MAIA) 	2015-2017 	Phase 3 (C) 	Dara-Rd 	Shorter PFS (primary endpoint)PFS30: 55.6% vs 70.6%(HR 1.79, 95% CI 1.37-2.33)Shorter OS2 (secondary endpoint)Median OS: NYR vs NYR(HR 1.47, 95% CI 1.16-1.89)
Puig et al. 2021 (GEM-CLARIDEX) 	2015-2019 	Phase 3 (C) 	BiRd 	Did not meet primary endpoint of PFSMedian PFS: 29 vs 23 mo(HR 0.78, 95% CI 0.55-1.09)
Usmani et al. 2019 (KEYNOTE-185) 	2016-01-07 to 2017-06-09	Phase 3 (C) 	Rd & Pembrolizumab	Did not meet primary endpoint of PFSMedian PFS: NYR vs NYR(HR 0.82, 95% CI 0.45-1.49)
1Reported efficacy for FIRST is based on the 2017 update.
2Reported efficacy for MAIA is based on the 2021 update.
Note: KEYNOTE-185 was closed early due to excess mortality in the experimental arm.
====Eligibility criteria====
*FIRST: patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation.
*MAIA: patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older.
====Targeted therapy====
*Lenalidomide (Revlimid) by the following renal function-based criteria:
**CrCl more than 50 mL/min/1.73m2: 25 mg PO once per day on days 1 to 21
**CrCl 30 to 50 mL/min/1.73m2: 10 mg PO once per day on days 1 to 21
**CrCl less than 30 mL/min/1.73m2: 15 mg PO once every other day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 75 years old: 40 mg PO once per day on days 1, 8, 15, 22
**Older than 75 years old: 20 mg PO once per day on days 1, 8, 15, 22
28-day cycles
====Dose and schedule modifications====
*FIRST: See supplemental appendix for further details of dose reductions from starting dose. 
*MAIA: Lenalidomide dosing for CrCl less than 30 mL/min/1.73m2 was not specified. Patients with BMI less than 18.5 were also given the reduced-dose dexamethasone.
===Regimen variant #6, indefinite with 35-day induction cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Zonder et al. 2010 (SWOG S0232)	2004-2007 	Phase 3 (E-esc)	Dexamethasone	Longer PFS (primary endpoint)PFS36: 52% vs 32%(HR not reported, p=0.002)
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.
====Targeted therapy====
*Lenalidomide (Revlimid) as follows:
**Cycles 1 to 3: 25 mg PO once per day on days 1 to 28
**Cycle 4 onwards: 25 mg PO once per day on days 1 to 21
====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 #7, indefinite 28-day cycles, first 4 with high-dose dex===
Study 	Dates of enrollment	Evidence
Rajkumar et al. 2005	2004 	Phase 2
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====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
====Supportive therapy====
*Thromboprophylaxis: Aspirin 80 mg or 325 mg PO once per day
28-day cycles
===References===
# Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005 Dec 15;106(13):4050-3. Epub 2005 Aug 23. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC
# ECOG E4A03: Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, Abonour R, Siegel DS, Katz M, Greipp PR; ECOG. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010 Jan;11(1):29-37. Epub 2009 Oct 21. Erratum in: Lancet Oncol. 2010 Jan;11(1):14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00098475
## Subgroup analysis: Jacobus SJ, Kumar S, Uno H, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, Williams ME, Siegel DS, Greipp PR, Rajkumar SV, Fonseca R. Impact of high-risk classification by FISH: an eastern cooperative oncology group (ECOG) study E4A03. Br J Haematol. 2011 Nov;155(3):340-8. Epub 2011 Sep 9. link to original article link to PMC article EuroPMC
# Retrospective: Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ, Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R. Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma. Am J Hematol. 2010 Sep;85(9):664-9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# SWOG S0232: Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BG, Barlogie B. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial (S0232). Blood. 2010 Dec 23;116(26):5838-41. Epub 2010 Sep 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00064038
# MPRvsMEL200: Palumbo A, Cavallo F, Gay F, Di Raimondo F, Ben Yehuda D, Petrucci MT, Pezzatti S, Caravita T, Cerrato C, Ribakovsky E, Genuardi M, Cafro A, Marcatti M, Catalano L, Offidani M, Carella AM, Zamagni E, Patriarca F, Musto P, Evangelista A, Ciccone G, Omedé P, Crippa C, Corradini P, Nagler A, Boccadoro M, Cavo M. Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014 Sep 4;371(10):895-905. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00551928
# FIRSTMM: Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. link to original article link to supplemental appendix dosing details in manuscript have been reviewed by our editors EuroPMC NCT00689936
## Update: Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016 Oct;34(30):3609-17. Epub 2016 Jun 20. link to original article EuroPMC
## Update: Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. Epub 2017 Nov 17. link to original article link to PMC article EuroPMC
# Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, Siniscalchi A, Magarotto V, Pour L, Carella A, Malfitano A, Petrò D, Evangelista A, Spada S, Pescosta N, Omedè P, Campbell P, Liberati AM, Offidani M, Ria R, Pulini S, Patriarca F, Hajek R, Spencer A, Boccadoro M, Palumbo A. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1617-29. Epub 2015 Nov 17. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01091831
# EMN01: Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01093196
# SWOG S0777: Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00644228
##Update: Durie BGM, Hoering A, Sexton R, Abidi MH, Epstein J, Rajkumar SV, Dispenzieri A, Kahanic SP, Thakuri MC, Reu FJ, Reynolds CM, Orlowski RZ, Barlogie B. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020 May 11;10(5):53. link to original article link to PMC article EuroPMC
# MAIA: Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Attal M, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Chiu C, Wang J, Van Rampelbergh R, Uhlar CM, Kobos R, Qi M, Usmani SZ; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-2115. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02252172
## HRQoL analysis: Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, Hulin C, Orlowski RZ, Nahi H, Mollee P, Ramasamy K, Roussel M, Jaccard A, Delforge M, Karlin L, Arnulf B, Chari A, He J, Ho KF, Van Rampelbergh R, Uhlar CM, Wang J, Kobos R, Gries KS, Fastenau J, Weisel K. Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial. J Clin Oncol. 2021 Jan 20;39(3):227-237. Epub 2020 Dec 16. link to original article link to PMC article EuroPMC
##Update: Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Wang J, Van Rampelbergh R, Uhlar CM, Tromp B, Delioukina M, Vermeulen J, Usmani SZ. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-1596. Epub 2021 Oct 13. link to original article EuroPMC
# KEYNOTE-185: Usmani SZ, Schjesvold F, Oriol A, Karlin L, Cavo M, Rifkin RM, Yimer HA, LeBlanc R, Takezako N, McCroskey RD, Lim ABM, Suzuki K, Kosugi H, Grigoriadis G, Avivi I, Facon T, Jagannath S, Lonial S, Ghori RU, Farooqui MZH, Marinello P, San-Miguel J; KEYNOTE-185 Investigators. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019 Sep;6(9):e448-e458. Epub 2019 Jul 18. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02579863
# TOURMALINE-MM2: Facon T, Venner CP, Bahlis NJ, Offner F, White D, Karlin L, Benboubker L, Rigaudeau S, Rodon P, Voog E, Yoon SS, Suzuki K, Shibayama H, Zhang X, Twumasi-Ankrah P, Yung G, Rifkin RM, Moreau P, Lonial S, Kumar SK, Richardson PG, Rajkumar SV. Oral ixazomib, lenalidomide, and dexamethasone for newly diagnosed transplant-ineligible multiple myeloma patients. Blood. 2021 Jul 1;137(26):3616-3628. Epub 2021 Mar 24. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01850524
#GEM-CLARIDEX: Puig N, Hernández MT, Rosiñol L, González E, de Arriba F, Oriol A, González-Calle V, Escalante F, de la Rubia J, Gironella M, Ríos R, García-Sánchez R, Arguiñano JM, Alegre A, Martín J, Gutiérrez NC, Calasanz MJ, Martín ML, del Carmen Couto M, Casanova M, Arnao M, Pérez-Persona E, Garzón S, González MS, Martín-Sánchez G, Ocio EM, Coleman M, Encinas C, Vale AM, Teruel AI, Cortés-Rodríguez M, Paiva B, Cedena MT, San-Miguel JF, Lahuerta JJ, Bladé J, Niesvizky R, Mateos MV. Lenalidomide and dexamethasone with or without clarithromycin in patients with multiple myeloma ineligible for autologous transplant: a randomized trial. Blood Cancer J. 2021 May 21;11(5):101. link to original article link to PMC article EuroPMC NCT02575144
#RV-MM-PI-0752: Larocca A, Bonello F, Gaidano G, D'Agostino M, Offidani M, Cascavilla N, Capra A, Benevolo G, Tosi P, Galli M, Marasca R, Giuliani N, Bernardini A, Antonioli E, Rota-Scalabrini D, Cellini C, Pompa A, Monaco F, Patriarca F, Caravita di Toritto T, Corradini P, Tacchetti P, Boccadoro M, Bringhen S. Dose/schedule-adjusted Rd-R vs continuous Rd for elderly, intermediate-fit patients with newly diagnosed multiple myeloma. Blood. 2021 Jun 3;137(22):3027-3036. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02215980
#ELOQUENT-1: Dimopoulos MA, Richardson PG, Bahlis NJ, Grosicki S, Cavo M, Beksaç M, Legieć W, Liberati AM, Goldschmidt H, Belch A, Magen H, Larocca A, Laubach JP, Petrucci MT, Reece D, White D, Mateos MV, Špička I, Lazaroiu M, Berdeja J, Kaufman JL, Jou YM, Ganetsky A, Popa McKiver M, Lonial S, Weisel K; ELOQUENT-1 investigators. Addition of elotuzumab to lenalidomide and dexamethasone for patients with newly diagnosed, transplantation ineligible multiple myeloma (ELOQUENT-1): an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2022 Jun;9(6):e403-e414. Epub 2022 May 9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01335399
#EMN20: NCT04096066
#King Faisal 2081-113: NCT01530594
==Lenalidomide & Prednisone (RP)==
RP: Revlimid (Lenalidomide) & Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence
Falco et al. 2012	2008-2009 	Phase 2
Note: this is a component of the sequential "RP-MPR-RP" protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Prednisone (Sterapred) 50 mg PO three times per week
====Supportive therapy====
*Thromboprophylaxis: Aspirin 100 mg PO once per day, taken during lenalidomide treatment (unclear from protocol if this also means off weeks)
*Antiviral prophylaxis if history of VZV.
28-day cycle for 4 cycles
====Subsequent treatment====
*MPR consolidation
===References===
# Falco P, Cavallo F, Larocca A, Rossi D, Guglielmelli T, Rocci A, Grasso M, Siez ML, De Paoli L, Oliva S, Molica S, Mina R, Gay F, Benevolo G, Musto P, Omedè P, Freilone R, Bringhen S, Carella AM, Gaidano G, Boccadoro M, Palumbo A. Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients. Leukemia. 2013 Mar;27(3):695-701. Epub 2012 Sep 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Thalidomide & Dexamethasone (TD)==
TD: Thalidomide & Dexamethasone
Thal-Dex: Thalidomide & Dexamethasone
===Regimen variant #1, 50 -> 200 mg/d, 6 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rosiñol et al. 2012 (GEM05/MENOS65)	2006-2009 	Phase 3 (C)	1. VTD 	Seems to have shorter PFS
Rosiñol et al. 2012 (GEM05/MENOS65)	2006-2009 	Phase 3 (C)	2. VBMCP/VBAD, then B	Not reported
Note: This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were less than or equal to 65 years of age with measurable serum and/or urine M protein.
====Targeted therapy====
*Thalidomide (Thalomid) as follows:
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
**Cycles 2 to 6: 200 mg PO once per day on days 1 to 28
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
====Supportive therapy====
*Low-molecular weight heparin or Aspirin recommended
28-day cycle for 6 cycles
===Regimen variant #2, 50 -> 200 mg/d, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rajkumar et al. 2008 (THAL-MM-003)	2003-2005 	Phase 3 (E-RT-esc)	Dexamethasone	Longer TTP (primary endpoint)Median TTP: 22.6 vs 6.5 mo(HR 0.43, 95% CI 0.32-0.58)
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.
====Targeted therapy====
*Thalidomide (Thalomid) as follows:
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
**Cycle 2 onwards: 200 mg PO once per day on days 1 to 28
====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 #3, 100 -> 200 mg/d, 3 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cavo et al. 2010 (GIMEMA MM-BO2005)	2006-2008 	Phase 3 (C)	VTD 	Shorter OS1 (secondary endpoint)Median OS: 110 vs NYR mo(HR 1.47, 95% CI 1.11-1.96)Lower CR rate/nCR rate (composite primary endpoint)
1Reported efficacy is based on the 2020 update.
Note: This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.
====Targeted therapy====
*Thalidomide (Thalomid) as follows:
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21
**Cycles 2 & 3: 200 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
21-day cycle for 3 cycles
====Subsequent treatment====
*Tandem MEL200 with auto HSCT consolidation, with interim Thal-Dex maintenance (see paper for details)
===Regimen variant #4, 100 -> 200 mg/d, 4 cycles===
Study 	Dates of enrollment	Evidence
Cavo et al. 2004 (Bologna 2002)	2002-2003 	Phase 2
====Targeted therapy====
*Thalidomide (Thalomid) as follows:
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to end of cycle
**Cycles 2 to 4: 200 mg PO once per day
====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
1-month cycle for 4 cycles
====Subsequent treatment====
*Bologna 2002, responders: Tandem high-dose melphalan, then autologous hematopoietic cell transplant consolidation''
===Regimen variant #5, 100 -> 400 mg/day===
Study 	Dates of enrollment	Evidence
Weber et al. 2003	1999-2001 	Phase 1/2
====Targeted therapy====
*Thalidomide (Thalomid) as follows:
**Cycle 1: 100 mg PO once per day on days 1 to 7, then 200 mg PO once per day on days 8 to 14, then 300 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 29
**Cycle 2 onwards: 400 mg PO once per day on days 1 to 29
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg/m2 PO once per day on days 1 to 4, 9 to 12, 17 to 20
29-day cycles
===Regimen variant #6, 200 mg/day===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Rajkumar et al. 2002 	Not reported 	Phase 2 	 	 	
Rajkumar et al. 2005 (ECOG E1A00)	2002-06 to 2003-04 	Phase 3 (E-RT-esc)	Dexamethasone	Seems to have higher RR within 4 months (primary endpoint)	Worse toxicity
Note: In ECOG E1A00 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.
====Targeted therapy====
*Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 28
====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
===References===
# Rajkumar SV, Hayman S, Gertz MA, Dispenzieri A, Lacy MQ, Greipp PR, Geyer S, Iturria N, Fonseca R, Lust JA, Kyle RA, Witzig TE. Combination therapy with thalidomide plus dexamethasone for newly diagnosed myeloma. J Clin Oncol. 2002 Nov 1;20(21):4319-23. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Weber D, Rankin K, Gavino M, Delasalle K, Alexanian R. Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. J Clin Oncol. 2003 Jan 1;21(1):16-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Bologna 2002: Cavo M, Zamagni E, Tosi P, Cellini C, Cangini D, Tacchetti P, Testoni N, Tonelli M, de Vivo A, Palareti G, Tura S, Baccarani M. First-line therapy with thalidomide and dexamethasone in preparation for autologous stem cell transplantation for multiple myeloma. Haematologica. 2004 Jul;89(7):826-31. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
## Sub-analysis: Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D, de Vivo A, Testoni N, Nicci C, Terragna C, Grafone T, Perrone G, Ceccolini M, Tura S, Baccarani M; Bologna 2002 study. Superiority of thalidomide and dexamethasone over vincristine-doxorubicindexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood. 2005 Jul 1;106(1):35-9. Epub 2005 Mar 10. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# ECOG E1A00: Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; ECOG. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006 Jan 20;24(3):431-6. Epub 2005 Dec 19. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00033332
# THAL-MM-003: Rajkumar SV, Rosiñol L, Hussein M, Catalano J, Jedrzejczak W, Lucy L, Olesnyckyj M, Yu Z, Knight R, Zeldis JB, Bladé J. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed multiple myeloma. J Clin Oncol. 2008 May 1;26(13):2171-7. Epub 2008 Mar 24. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00057564
# 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. Erratum in: Lancet. 2011 Nov 26;378(9806):1846. link to original article EuroPMC NCT01134484
## Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, Galli M, Di Raimondo F, Crippa C, Boccadoro M, Barbato S, Tosi P, Narni F, Montefusco V, Testoni N, Spadano A, Terragna C, Pescosta N, Marzocchi G, Cellini C, Galieni P, Ronconi S, Gobbi M, Catalano L, Lazzaro A, De Sabbata G, Cangialosi C, Ciambelli F, Musto P, Elice F, Cavo M; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto Italian Myeloma Network). Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol. 2020 Dec;7(12):e861-e873. link to original article EuroPMC
# GEM05/MENOS65: Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; PETHEMA; GEM. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00461747
## Update: Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=First-line therapy, triplets=
==BBD==
BBD: Bendamustine, Bortezomib, Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence
Berdeja et al. 2017 (SCRI MM 23)	2010-2014 	Phase 2
Note: this is the modified treatment schema.
====Chemotherapy====
*Bendamustine 80 mg/m2 IV once per day on days 1 & 2
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 8, 15
====Supportive therapy====
*Mandatory VZV prophylaxis
28-day cycle for 8 cycles
====Subsequent treatment====
*Vd maintenance
===References===
# SCRI MM 23: Berdeja JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA Jr, Boccia RV, Donnellan W, Flinn I. Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J Haematol. 2017 Apr;177(2):254-262. Epub 2017 Feb 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01056276
==CPR==
CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Magarotto et al. 2016 (EMN01)	2009-2012 	Phase 3 (E-esc)	1. MPR 	Might have shorter PFS (primary endpoint)
Magarotto et al. 2016 (EMN01)	2009-2012 	Phase 3 (E-esc)	2. Rd 	Did not meet primary endpoint of PFS
Note: This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This is the dosing used after a mid-protocol amendment.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 50 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Prednisone (Sterapred) 25 mg PO once every other day
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Supportive therapy====
*Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
28-day cycle for 9 cycles
====Subsequent treatment====
*Lenalidomide versus RP maintenance
===References===
# EMN01: Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01093196
==CRd==
CRd: Cyclophosphamide, Revlimid (Lenalidomide), low-dose dexamethasone
Rdc: Revlimid (Lenalidomide), low-dose dexamethasone, low-dose cyclophosphamide
===Regimen variant #1, Rdc===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Jackson et al. 2021 (UK NCRI Myeloma XI+)	2013-2016 	Phase 3 (C)	1. KRdc 	Shorter PFS
Jackson et al. 2021 (UK NCRI Myeloma XI+)	2013-2016 	Phase 3 (C)	2. Tdc 	Not reported
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1 & 8
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 12 to 15
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for at least 4 cycles
====Subsequent treatment====
*UK NCRI Myeloma XI+, VGPR or better: Melphalan, then auto HSCT consolidation, then Lenalidomide maintenance versus Observation
*UK NCRI Myeloma XI+, Minimal or partial response: CVD consolidation versus no further therapy
*UK NCRI Myeloma XI+, SD/PD: CVD
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Kumar et al. 2011 (RV-MM-PI-0116)	2006-2008 	Phase 2
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Supportive therapy====
*Aspirin 325 mg PO once per day
*LMWH or Warfarin (Coumadin) for patients with history of thrombotic events or at "higher" risk
 
28-day cycle for 4 to 12 cycles
====Subsequent treatment====
*At physician discretion, patient could proceed to lenalidomide maintenance +/- dexamethasone, after the 12th cycle, until progression
===References===
# RV-MM-PI-0116: Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, Laumann K, Greipp PR, Lust JA, Gertz MA, Zeldenrust SR, Bergsagel PL, Reeder CB, Witzig TE, Fonseca R, Russell SJ, Mikhael JR, Dingli D, Rajkumar SV, Dispenzieri A. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol. 2011 Aug;86(8):640-5. Epub 2011 May 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00478218
# UK NCRI Myeloma XI+: Jackson GH, Pawlyn C, Cairns DA, de Tute RM, Hockaday A, Collett C, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Rocci A, Snowden JA, Jenner MW, Cook G, Russell NH, Drayson MT, Gregory WM, Kaiser MF, Owen RG, Davies FE, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial. PLoS Med. 2021 Jan 11;18(1):e1003454. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01554852
==CTD==
CTD: Cyclophosphamide, Thalidomide, Dexamethasone
CTDa: Cyclophosphamide, Thalidomide, Dexamethasone, attenuated
Tdc: Thalidomide, low-dose dexamethasone, low-dose cyclophosphamide
===Regimen variant #1, CTD===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX)	2003-2007 	Phase 3 (E-switch-ooc)	CVAD 	Not reported
Note: This was an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference. Thalidomide dose was only increased if the starting dose was tolerated.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 12 to 15
====Targeted therapy====
*Thalidomide (Thalomid) as follows:
**Cycle 1: 100 mg PO once per day on days 1 to 21
**Cycle 2 onwards: 200 mg PO once per day on days 1 to 21
====Supportive therapy====
*Venous thromboembolism (VTE) prophylaxis was given at physician discretion, but it was suggested that low-risk patients receive Aspirin and high-risk patients receive Warfarin (Coumadin) or low molecular weight heparin according to risk categories as described by Palumbo A et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22(2):414–23. link to original article EuroPMC
*Patients in the study were randomized to one of the following until progression:
**Sodium clodronate (Bonefos) 1600 mg PO once per day 
**Zoledronic acid (Zometa) 4 mg IV once every 21 to 28 days
21-day cycle for 4 to 6 cycles until maximum response
====Subsequent treatment====
*MRC Myeloma IX, responding patients: High-dose melphalan and autologous hematopoietic cell transplant consolidation
===Regimen variant #2, CTDa===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX)	2003-2007 	Phase 3 (E-esc)	MP 	Not reported
Note: This was a nonintensive treatment pathway, as determined by performance status, informed discussion, and patient preference. Thalidomide dose was increased only if the prior dose was tolerated.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 15 to 18
====Targeted therapy====
*Thalidomide (Thalomid) as follows:
**Cycle 1: 50 mg PO once per day on days 1 to 28
**Cycle 2: 100 mg PO once per day on days 1 to 28
**Cycle 3: 150 mg PO once per day on days 1 to 28
**Cycles 4 to 9: 200 mg PO once per day on days 1 to 28
====Supportive therapy====
*For the first 12 weeks of treatment, thromboprophylaxis was recommended, for example: Warfarin (Coumadin) or low molecular weight heparin
*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
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hungria et al. 2015 (GBRAM0002)	2006-2013 	Phase 3 (E-switch-ic)	1. MPT 	Might have higher ORR (primary endpoint)
Hungria et al. 2015 (GBRAM0002)	2006-2013 	Phase 3 (E-switch-ic)	2. TD 	Not reported
Note: the TD arm was close prematurely and no comparisons were made.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 50 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 15 to 18
**Cycles 3 to 9: 40 mg PO once per day on days 1 to 4
====Targeted therapy====
*Thalidomide (Thalomid) 200 mg PO once per day
28-day cycle for up to 9 cycles
===References===
# MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article EuroPMC ISRCTN68454111
## Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article EuroPMC
# GBRAM0002: Hungria VT, Crusoé EQ, Maiolino A, Bittencourt R, Fantl D, Maciel JF, Pessoa de Magalhaes RJ, Almeida MS, Cury P, Hisgashi F, Peres AL, Chiattone CS. Phase 3 trial of three thalidomide-containing regimens in patients with newly diagnosed multiple myeloma not transplant-eligible. Ann Hematol. 2016 Jan;95(2):271-8. Epub 2015 Oct 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01532856
#GBRAM003r: NCT03402295
#NCRI Myeloma XI: NCT01554852
==Dara-Rd==
Dara-Rd: Daratumumab, Revlimid (Lenalidomide), Dexamethasone
DRd: Daratumumab, Revlimid (Lenalidomide), Dexamethasone
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Facon et al. 2019 (MAIA)	2015-2017 	Phase 3 (E-RT-esc)	Rd 	Longer PFS (primary endpoint)PFS30: 70.6% vs 55.6%(HR 0.56, 95% CI 0.43-0.73)Longer OS1 (secondary endpoint)Median OS: NYR vs NYR(HR 0.68, 95% CI 0.53-0.86)
1Reported efficacy is based on the 2021 update.
Note: This regimen was intended for patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older.
====Targeted therapy====
*Daratumumab (Darzalex) as follows:
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15
**Cycle 7 onwards: 16 mg/kg IV once on day 1
*Lenalidomide (Revlimid) by the following renal function-based criteria:
**CrCl more than 50 mL/min/1.73m2: 25 mg PO once per day on days 1 to 21
**CrCl 30 to 50 mL/min/1.73 m2: 10 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age- and BMI-based criteria:
**75 years old and younger AND BMI 18.5 or more: 40 mg PO once per day on days 1, 8, 15, 22
**Older than 75 years old OR BMI less than 18.5: 20 mg PO once per day on days 1, 8, 15, 22
28-day cycles
===References===
# MAIA: Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Attal M, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Chiu C, Wang J, Van Rampelbergh R, Uhlar CM, Kobos R, Qi M, Usmani SZ; MAIA Trial Investigators. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019 May 30;380(22):2104-2115. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02252172
## HRQoL analysis: Perrot A, Facon T, Plesner T, Usmani SZ, Kumar S, Bahlis NJ, Hulin C, Orlowski RZ, Nahi H, Mollee P, Ramasamy K, Roussel M, Jaccard A, Delforge M, Karlin L, Arnulf B, Chari A, He J, Ho KF, Van Rampelbergh R, Uhlar CM, Wang J, Kobos R, Gries KS, Fastenau J, Weisel K. Health-Related Quality of Life in Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma: Findings From the Phase III MAIA Trial. J Clin Oncol. 2021 Jan 20;39(3):227-237. Epub 2020 Dec 16. link to original article link to PMC article EuroPMC
##Update: Facon T, Kumar SK, Plesner T, Orlowski RZ, Moreau P, Bahlis N, Basu S, Nahi H, Hulin C, Quach H, Goldschmidt H, O'Dwyer M, Perrot A, Venner CP, Weisel K, Mace JR, Raje N, Tiab M, Macro M, Frenzel L, Leleu X, Ahmadi T, Wang J, Van Rampelbergh R, Uhlar CM, Tromp B, Delioukina M, Vermeulen J, Usmani SZ. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Nov;22(11):1582-1596. Epub 2021 Oct 13. link to original article EuroPMC
# EQUATE: NCT04566328
==IRd==
IRd: Ixazomib, Revlimid (Lenalidomide), low-dose dexamethasone
===Regimen variant #1, indefinite with dose-reduced dexamethasone===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Facon et al. 2021 (TOURMALINE-MM2)	2013-2015 	Phase 3 (E-esc)	Rd 	Might have longer PFS (primary endpoint)Median PFS: 35.3 vs 21.8 mo(HR 0.83, 95% CI 0.68-1.02)
Note: this variant was intended for patients older than 75 years. Patients were ineligible for autologous HSCT due to age or comorbidities.
====Targeted therapy====
*Ixazomib (Ninlaro) as follows:
**Cycles 1 to 18: 4 mg PO once per day on days 1, 8, 15
**Cycle 19 onwards: 3 mg PO once per day on days 1, 8, 15
*Lenalidomide (Revlimid) as follows:
**Cycles 1 to 18: 25 mg PO once per day on days 1 to 21
**Cycle 19 onwards: 10 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 18: 20 mg PO once per day on days 1, 8, 15, 22
28-day cycles
===Regimen variant #2, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Facon et al. 2021 (TOURMALINE-MM2)	2013-2015 	Phase 3 (E-esc)	Rd 	Might have longer PFS (primary endpoint)Median PFS: 35.3 vs 21.8 mo(HR 0.83, 95% CI 0.68-1.02)
Note: Patients were ineligible for autologous HSCT due to age or comorbidities.
====Targeted therapy====
*Ixazomib (Ninlaro) as follows:
**Cycles 1 to 18: 4 mg PO once per day on days 1, 8, 15
**Cycle 19 onwards: 3 mg PO once per day on days 1, 8, 15
*Lenalidomide (Revlimid) as follows:
**Cycles 1 to 18: 25 mg PO once per day on days 1 to 21
**Cycle 19 onwards: 10 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 18: 40 mg PO once per day on days 1, 8, 15, 22
28-day cycles
===Regimen variant #3, limited duration===
Study 	Dates of enrollment	Evidence
Kumar et al. 2014 (C16005)	2010-2012 	Phase 1/2
Note: This is the MTD dose of C16005.
====Targeted therapy====
*Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycle for up to 12 cycles 
====Subsequent treatment====
*Transplant-eligible patients could proceed to autologous hematopoietic cell transplant after 6 cycles
*C16005, patients who did not undergo transplant: ixazomib maintenance after the 12th cycle
===References===
# C16005: Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-12. Epub 2014 Nov 14. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01217957
# TOURMALINE-MM2: Facon T, Venner CP, Bahlis NJ, Offner F, White D, Karlin L, Benboubker L, Rigaudeau S, Rodon P, Voog E, Yoon SS, Suzuki K, Shibayama H, Zhang X, Twumasi-Ankrah P, Yung G, Rifkin RM, Moreau P, Lonial S, Kumar SK, Richardson PG, Rajkumar SV. Oral ixazomib, lenalidomide, and dexamethasone for newly diagnosed transplant-ineligible multiple myeloma patients. Blood. 2021 Jul 1;137(26):3616-3628. Epub 2021 Mar 24. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01850524
# FiTNEss: NCT03720041
==Isa-Rd==
Isa-Rd: Isatuximab, Revlimid (Lenalidomide), low-dose dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Leleu et al. 2024 (BENEFIT)	2021-09-07 to 2022-09-02	Phase 3 (C)	Isa-RVd 	Lower MRD- at 18 mo (primary endpoint)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Targeted therapy====
*Isatuximab (Sarclisa) as follows:
**Cycle 1: 10 mg/kg IV once per day on days 1, 8, 15, 22
**Cycles 2 to 12: 10 mg/kg IV once per day on days 1 & 15
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 12 cycles
====Subsequent treatment====
*Len-Isa maintenance
===References===
#BENEFIT: Leleu X, Hulin C, Lambert J, Bobin A, Perrot A, Karlin L, Roussel M, Montes L, Cherel B, Chalopin T, Slama B, Chretien ML, Laribi K, Dingremont C, Roul C, Mariette C, Rigaudeau S, Calmettes C, Dib M, Tiab M, Vincent L, Delaunay J, Santagostino A, Macro M, Bourgeois E, Orsini-Piocelle F, Gay J, Bareau B, Bigot N, Vergez F, Lebreton P, Tabrizi R, Waultier-Rascalou A, Frenzel L, Le Calloch R, Chalayer E, Braun T, Lachenal F, Corm S, Kennel C, Belkhir R, Bladé JS, Joly B, Richez-Olivier V, Gardeney H, Demarquette H, Robu-Cretu D, Garderet L, Newinger-Porte M, Kasmi A, Royer B, Decaux O, Arnulf B, Belhadj K, Touzeau C, Mohty M, Manier S, Moreau P, Avet-Loiseau H, Corre J, Facon T. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. 2024 Aug;30(8):2235-2241. Epub 2024 Jun 3. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04751877
==KCD==
KCD: Kyprolis (Carfilzomib), Cyclophosphamide, Dexamethasone
CCyd: Carfilzomib, Cyclophosphamide, dexamethasone
KCyd: Kyprolis (Carfilzomib), Cyclophosphamide, dexamethasone
===Regimen variant #1, bi-weekly carfilzomib===
Study 	Dates of enrollment 	Evidence
Bringhen et al. 2014 (IST-CAR-506)	2011-06-21 to 2012-09-15	Phase 2
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1 & 2 then 36 mg/m2 IV once per day on days 8, 9, 15, 16
**Cycles 2 to 9: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 9 cycles
====Subsequent treatment====
*Carfilzomib maintenance
===Regimen variant #2, weekly carfilzomib ("wKCyd")===
Study 	Dates of enrollment 	Evidence
Bringhen et al. 2017 (IST-CAR-561)	2013-04-10 to 2015-08-24	Phase 1/2
Note: this is the MTD established for the phase 2 portion of the trial.
====Targeted therapy====
*Carfilzomib (Kyprolis) 70 mg/m2 IV once per day on days 1, 8, 15
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 9 cycles
====Subsequent treatment====
*Carfilzomib maintenance
===References===
# IST-CAR-506: Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, Musto P, Boccadifuoco L, Offidani M, Omedé P, Gentilini F, Ciccone G, Benevolo G, Genuardi M, Montefusco V, Oliva S, Caravita T, Tacchetti P, Boccadoro M, Sonneveld P, Palumbo A. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood. 2014 Jul 3;124(1):63-9. Epub 2014 May 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01346787
# IST-CAR-561: Bringhen S, D'Agostino M, De Paoli L, Montefusco V, Liberati AM, Galieni P, Grammatico S, Muccio VE, Esma F, De Angelis C, Musto P, Ballanti S, Offidani M, Petrucci MT, Gaidano G, Corradini P, Palumbo A, Sonneveld P, Boccadoro M. Phase 1/2 study of weekly carfilzomib, cyclophosphamide, dexamethasone in newly diagnosed transplant-ineligible myeloma. Leukemia. 2018 Apr;32(4):979-985. Epub 2017 Nov 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01857115
==KMP==
KMP: Kyprolis (Carfilzomib), Melphalan, Prednisone
CMP: Carfilzomib, Melphalan, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Moreau et al. 2015 (CARMYSAP)	2010-2012 	Phase 1/2 	 	
Facon et al. 2019 (CLARION) 	2013-2015 	Phase 3 (E-switch-ic)	VMP 	Did not meet primary endpoint of PFSMedian PFS: 22.3 vs 22.1 mo(HR 0.91, 95% CI 0.75-1.10)
Note: CARMYSAP was open to patients older than 65 years of age. Although not explicitly stated, this is considered to be a transplant ineligible population in France. The carfilzomib dose of 36 mg/m2 was considered to be the MTD in CARMYSAP. CLARION was open to transplant ineligible patients.
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV over 30 minutes once per day on days 1 & 2, then 36 mg/m2 IV once per day on days 8, 9, 22, 23, 29, 30
**Cycles 2 to 9: 36 mg/m2 IV over 30 minutes once per day on days 1, 2, 8, 9, 22, 23, 29, 30
====Chemotherapy====
*Melphalan (Alkeran) 9 mg/m2/day PO on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 4
42-day cycle for 9 cycles
===References===
# CARMYSAP: Moreau P, Kolb B, Attal M, Caillot D, Benboubker L, Tiab M, Touzeau C, Leleu X, Roussel M, Chaleteix C, Planche L, Chiffoleau A, Fortin J, Avet-Loiseau H, Mary JY, Hulin C, Facon T. Phase 1/2 study of carfilzomib plus melphalan and prednisone in patients aged over 65 years with newly diagnosed multiple myeloma. Blood. 2015 May 14;125(20):3100-4. Epub 2015 Mar 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01279694
# CLARION: Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos M, Hajek R, Pour L, Jurczyszyn A, Qiu L, Klippel Z, Zahlten-Kumeli A, Osman M, Paiva B, San-Miguel J. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019 May 2;133(18):1953-1963. Epub 2019 Feb 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01818752
==KRd==
KRd: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), low-dose dexamethasone
CRd: Carfilzomib, Revlimid (Lenalidomide), low-dose dexamethasone
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Korde et al. 2016 (NCI 11-C-0221)	2011-2013 	Phase 2
Note: The minimal difference between this and variant #2 below is the steroid dosing.
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 36 mg/m2 IV once per day on days 8, 9, 15, 16
**Cycles 2 to 8: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycle 1: 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
**Cycles 2 to 4: 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
**Cycles 5 to 8: 10 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
28-day cycle for 8 cycles
====Subsequent treatment====
*Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant. 
*If transplant was not undertaken, patients proceeded to lenalidomide maintenance after the 8th cycle
</div>
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Jakubowiak et al. 2012 (UMCC 2009.056)	2009-2011 	Phase 1/2
Note: This is the MTD dosing in this phase I/II trial.
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 36 mg/m2 IV once per day on days 8, 9, 15, 16
**Cycles 2 to 8: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 4: 40 mg (route not specified) once per day on days 1, 8, 15, 22
**Cycles 1 & 2: 4 mg IV or PO once per day on days 2, 9, 16 (in addition to above, at clinician's discretion)
**Cycles 5 to 8: 20 mg (route not specified) once per day on days 1, 8, 15, 22
28-day cycle for 8 cycles
====Subsequent treatment====
*Transplant eligible patients underwent stem cell collection after the 4th cycle but were not obligated to proceed to transplant 
*If transplant was not undertaken, patients proceeded to CRd maintenance after the 8th cycle
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kumar et al. 2020 (ENDURANCE)	2013-2019 	Phase 3 (E-switch-ic)	RVD 	Did not meet primary endpoint of PFSMedian PFS: 34.6 vs 34.4 mo(HR 1.04, 95% CI 0.83-1.31)
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 36 mg/m2 IV once per day on days 8, 9, 15, 16
**Cycles 2 to 8: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
**Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
**Cycles 9 to 12: 10 mg PO once per day on days 1, 2, 8, 9
28-day cycle for 9 cycles
====Subsequent treatment====
*Lenalidomide x 2 y versus indefinite Lenalidomide maintenance
===References===
# UMCC 2009.056: Jakubowiak AJ, Dytfeld D, Griffith KA, Lebovic D, Vesole DH, Jagannath S, Al-Zoubi A, Anderson T, Nordgren B, Detweiler-Short K, Stockerl-Goldstein K, Ahmed A, Jobkar T, Durecki DE, McDonnell K, Mietzel M, Couriel D, Kaminski M, Vij R. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012 Aug 30;120(9):1801-9. Epub 2012 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01029054
# NCI 11-C-0221: Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, Tageja N, Kazandjian D, Mailankody S, Wu P, Morrison C, Costello R, Zhang Y, Burton D, Mulquin M, Zuchlinski D, Lamping L, Carpenter A, Wall Y, Carter G, Cunningham SC, Gounden V, Sissung TM, Peer C, Maric I, Calvo KR, Braylan R, Yuan C, Stetler-Stevenson M, Arthur DC, Kong KA, Weng L, Faham M, Lindenberg L, Kurdziel K, Choyke P, Steinberg SM, Figg W, Landgren O. Treatment With carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015 Sep;1(6):746-54. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01402284
# ENDURANCE: Kumar SK, Jacobus SJ, Cohen AD, Weiss M, Callander N, Singh AK, Parker TL, Menter A, Yang X, Parsons B, Kumar P, Kapoor P, Rosenberg A, Zonder JA, Faber E Jr, Lonial S, Anderson KC, Richardson PG, Orlowski RZ, Wagner LI, Rajkumar SV. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020 Oct;21(10):1317-1330. Epub 2020 Aug 28. link to original article link to PMC article EuroPMC NCT01863550
#COBRA: NCT03729804
#EMN20: NCT04096066
</div>
==KTD==
KTd: Kyprolis (Carfilzomib), Thalidomide, Dexamethasone
===Regimen variant #1, 20/27===
Study 	Dates of enrollment	Evidence
Sonneveld et al. 2014 (CARTHADEX)	2010-2013 	Phase 2
Note: Three cohorts are reported; optimal dose of carfilzomib is not described.
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 27 mg/m2 IV once per day on days 8, 9, 15, 16 
**Cycles 2 to 4: 27 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
*Thalidomide (Thalomid) 200 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 4 cycles
====Subsequent treatment====
*High-dose melphalan with stem cell rescue consolidation
===Regimen variant #2, 20/36===
Study 	Dates of enrollment	Evidence
Sonneveld et al. 2014 (CARTHADEX)	2010-2013 	Phase 2
Note: Three cohorts are reported; optimal dose of carfilzomib is not described.
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 36 mg/m2 IV once per day on days 8, 9, 15, 16 
**Cycles 2 to 4: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
*Thalidomide (Thalomid) 200 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 4 cycles
====Subsequent treatment====
*High-dose melphalan with stem cell rescue consolidation
===Regimen variant #3, 20/45===
Study 	Dates of enrollment	Evidence
Sonneveld et al. 2014 (CARTHADEX)	2010-2013 	Phase 2
Note: Three cohorts are reported; optimal dose of carfilzomib is not described.
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 45 mg/m2 IV once per day on days 8, 9, 15, 16 
**Cycles 2 to 4: 45 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
*Thalidomide (Thalomid) 200 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 4 cycles
====Subsequent treatment====
*High-dose melphalan with stem cell rescue consolidation
===References===
# CARTHADEX: Sonneveld P, Asselbergs E, Zweegman S, van der Holt B, Kersten MJ, Vellenga E, van Marwijk-Kooy M, Broyl A, de Weerdt O, Lonergan S, Palumbo A, Lokhorst H. Phase 2 study of carfilzomib, thalidomide and dexamethasone as induction/consolidation therapy for newly diagnosed multiple myeloma. Blood. 2015 Jan 15;125(3):449-56. Epub 2014 Nov 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NTR2422
==MPR==
MPR: Melphalan, Prednisone, Revlimid (Lenalidomide)
MPL: Melphalan, Prednisone, Lenalidomide
===Regimen variant #1, 0.13/1.5/10===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Magarotto et al. 2016 (EMN01)	2009-2012 	Phase 3 (E-esc)	1. CPR 	Might have longer PFS (primary endpoint)
Magarotto et al. 2016 (EMN01)	2009-2012 	Phase 3 (E-esc)	2. Rd 	Might have longer PFS (primary endpoint)
Note: This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant was intended for patients older than 75.
====Chemotherapy====
*Melphalan (Alkeran) 0.13 mg/kg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 1.5 mg/kg PO once per day on days 1 to 4
====Targeted therapy====
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
====Supportive therapy====
*Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
28-day cycle for 9 cycles
====Subsequent treatment====
*Lenalidomide versus Lenalidomide & Prednisone maintenance
===Regimen variant #2, 0.18/1.5/10===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Magarotto et al. 2016 (EMN01)	2009-2012 	Phase 3 (E-esc)	1. CPR 	Might have longer PFS (primary endpoint)
Magarotto et al. 2016 (EMN01)	2009-2012 	Phase 3 (E-esc)	2. Rd 	Might have longer PFS (primary endpoint)
Note: This regimen is intended for patients who were ineligible for high-dose therapy plus stem cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant was intended for patients aged 65 to 75.
====Chemotherapy====
*Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 1.5 mg/kg PO once per day on days 1 to 4
====Targeted therapy====
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
====Supportive therapy====
*Aspirin or LMWH or Warfarin (Coumadin) at physician's discretion (mandatory)
28-day cycle for 9 cycles
====Subsequent treatment====
*Lenalidomide versus Lenalidomide & Prednisone maintenance
===Regimen variant #3, 0.18/2/10===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Palumbo et al. 2007a 	2005 	Phase 2 	 	
Palumbo et al. 2012 (MM-015) 	2007-02 to 2008-09 	Phase 3 (E-esc) 	1. MP 	Longer PFS (primary endpoint)
Palumbo et al. 2012 (MM-015) 	2007-02 to 2008-09 	Phase 3 (E-esc) 	2. MPR 	Longer PFS (primary endpoint)
Zweegman et al. 2016 (HOVON87/NMSG18)	2009-2012 	Phase 3 (E-switch-ic)	MPT-T 	Might have longer PFS (primary endpoint)Median PFS: 23 vs 20 mo(HR 0.87, 95% CI 0.72-1.04)
Note: In Palumbo et al. 2007a this regimen was intended for newly diagnosed multiple myeloma patients greater than or equal to 65 years, or younger if ineligible for high-dose therapy. In MM-015 this regimen was intended for patients with symptomatic, measurable, newly diagnosed multiple myeloma who were not candidates for transplantation (greater than or equal to 65 years of age). In HOVON87/NMSG18 this regimen was intended for patients greater than 65 years of age or patients less than or equal to 65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.
====Chemotherapy====
*Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
====Targeted therapy====
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
====Supportive therapy====
*HOVON87/NMSG18:
**Aspirin 75 or 80 mg PO once per day or Carbasalate calcium (Ascal) 100 mg PO once per day
***Patients with a history of VTE received LMWH instead
**Bisphosphonates at physician discretion
**Prophylactic antibiotics at physician discretion
*MM-015: Aspirin 75 to 100 mg PO once per day
*Palumbo et al. 2007a: Ciprofloxacin (Cipro) 500 mg PO twice per day and Aspirin 100 mg PO once per day
28-day cycle for 9 cycles
====Subsequent treatment====
*Lenalidomide maintenance
===Regimen variant #4, 5/100/10===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Stewart et al. 2015 (ECOG E1A06)	2008-2011 	Phase 3 (E-switch-ic)	MPT-T 	Seems to have non-inferior PFS (primary endpoint)
Note: This regimen was intended for patients who were greater than or equal to 65 years or were less than 65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.
====Chemotherapy====
*Melphalan (Alkeran) 5 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
====Targeted therapy====
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
====Supportive therapy====
*Aspirin was required (dose not specified)
**Full anticoagulation was used for patients at "higher risk" for DVT
*Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"
28-day cycle for 12 cycles
====Subsequent treatment====
*Lenalidomide maintenance
===References===
# Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, Crippa C, Ciccone G, Omedè P, Ambrosini MT, Gay F, Bringhen S, Musto P, Foà R, Knight R, Zeldis JB, Boccadoro M, Petrucci MT; GIMEMA--Italian Multiple Myeloma Network. Melphalan, prednisone, and lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA--Italian Multiple Myeloma Network. J Clin Oncol. 2007 Oct 1;25(28):4459-65. Epub 2007 Sep 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# MM-015: Palumbo A, Hajek R, Delforge M, Kropff M, Petrucci MT, Catalano J, Gisslinger H, Wiktor-Jedrzejczak W, Zodelava M, Weisel K, Cascavilla N, Iosava G, Cavo M, Kloczko J, Bladé J, Beksac M, Spicka I, Plesner T, Radke J, Langer C, Ben Yehuda D, Corso A, Herbein L, Yu Z, Mei J, Jacques C, Dimopoulos MA; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012 May 10;366(19):1759-69. Erratum in: N Engl J Med. 2012 Jul 19;367(3):285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00405756
# ECOG E1A06: Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00602641
# EMN01: Magarotto V, Bringhen S, Offidani M, Benevolo G, Patriarca F, Mina R, Falcone AP, De Paoli L, Pietrantuono G, Gentili S, Musolino C, Giuliani N, Bernardini A, Conticello C, Pulini S, Ciccone G, Maisnar V, Ruggeri M, Zambello R, Guglielmelli T, Ledda A, Liberati AM, Montefusco V, Hajek R, Boccadoro M, Palumbo A. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016 Mar 3;127(9):1102-8. Epub 2016 Jan 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01093196
# HOVON87/NMSG18: Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2007-004007-34
##HRQoL analysis: Nielsen LK, Stege C, Lissenberg-Witte B, van der Holt B, Mellqvist UH, Salomo M, Bos G, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden A, Deenik W, Coenen J, Hinge M, Klein S, Tanis B, Szatkowski D, Brouwer R, Westerman M, Leys R, Sinnige H, Haukås E, van der Hem K, Durian M, Gimsing P, van de Donk N, Sonneveld P, Waage A, Abildgaard N, Zweegman S. Health-related quality of life in transplant ineligible newly diagnosed multiple myeloma patients treated with either thalidomide or lenalidomide-based regimen until progression: a prospective, open-label, multicenter, randomized, phase 3 study. Haematologica. 2020 Jun;105(6):1650-1659. Epub 2019 Sep 12. link to original article link to PMC article EuroPMC
==MPT==
MPT: Melphalan, Prednisone, Thalidomide
===Regimen variant #1, 0.72/8/200===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zweegman et al. 2016 (HOVON87/NMSG18)	2009-2012 	Phase 3 (C)	MPR-R 	Did not meet primary endpoint of PFS
Note: This regimen was intended for patients greater than 65 years of age or patients less than or equal to 65 of age and not eligible for high-dose chemotherapy and peripheral stem cell transplantation with newly diagnosed symptomatic MM.
====Chemotherapy====
*Melphalan (Alkeran) 0.18 mg/kg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 2 mg/kg PO once per day on days 1 to 4
====Targeted therapy====
*Thalidomide (Thalomid) 200 mg PO once per day 
====Supportive therapy====
*Aspirin 75 or 80 mg PO once per day or Carbasalate calcium (Ascal) 100 mg PO once per day
**Patients with a history of VTE received LMWH instead
*Bisphosphonates at physician discretion
*Prophylactic antibiotics at physician discretion
28-day cycle for 9 cycles
====Subsequent treatment====
*Thalidomide maintenance
===Regimen variant #2, 36/400/100===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Stewart et al. 2015 (ECOG E1A06)	2008-2011 	Phase 3 (C)	mPR-R 	Seems to have non-inferior PFS
Note: This regimen was intended for patients who were greater than or equal to 65 years or were less than 65 years and were not candidates for autologous hematopoietic cell transplantation or had declined transplant.
====Chemotherapy====
*Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 4
====Targeted therapy====
*Thalidomide (Thalomid) 100 mg PO once per day 
====Supportive therapy====
*Aspirin was required (dose not specified)
**Full anticoagulation was used for patients at "higher risk" for DVT
*Pamidronate (Aredia) 90 mg IV once per month recommended for patients with "active bone disease"
28-day cycle for 12 cycles
====Subsequent treatment====
*Thalidomide maintenance
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Benboubker et al. 2014 (FIRSTMM)	2008-2011 	Phase 3 (C)	1. Rd 	Shorter OS1
Benboubker et al. 2014 (FIRSTMM)	2008-2011 	Phase 3 (C)	2. Rd18 	Might have shorter OS
1Reported efficacy compared to Rd continuous is based on the 2017 update.
Note: This regimen was intended for patients who had previously untreated, symptomatic, and measurable multiple myeloma and either were greater than or equal to 65 years of age or were less than 65 years of age and ineligible for stem-cell transplantation. See supplemental appendix for further details of dose reductions from starting dose.
====Chemotherapy====
*Melphalan (Alkeran) by the following age- and laboratory-based criteria:
**Younger than 75 years old AND ANC 1500/μL or more AND platelet count 100 x 109/L or more: 0.25 mg/kg PO once per day on days 1 to 4
**Older than 75 years old AND ANC 1500/μL or more AND platelet count 100 x 109/L or more: 0.2 mg/kg PO once per day on days 1 to 4
**Younger than 75 years old AND ANC 1000 up to 1500/μL OR platelet count 50 up to 100 x 109/L: 0.125 mg/kg PO once per day on days 1 to 4
**Older than 75 years old AND ANC 1000 up to 1500/μL OR platelet count 50 up to 100 x 109/L: 0.1 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
====Targeted therapy====
*Thalidomide (Thalomid) by the following age-based criteria:
**Younger than 75 years old: 200 mg PO once per day
**Older than 75 years old: 100 mg PO once per day
42-day cycle for 12 cycles
===Regimen variant #4, 36/240/100===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Beksac et al. 2010 (TMSG-2005-001)	2006-2009 	Phase 3 (E-esc)	MP 	Seems to have higher ORR (primary endpoint)
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
====Targeted therapy====
*Thalidomide (Thalomid) 100 mg PO once per day 
42-day cycle for 9 cycles
===Regimen variant #5, 1/400/400===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Waage et al. 2010 (NMSG12)	2002-2007 	Phase 3 (E-esc)	MP 	Did not meet primary endpoint of OS
Note: 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
====Targeted therapy====
*Thalidomide (Thalomid) as follows:
**Cycle 1: 200 mg PO once per day for one week, then increased to 400 mg PO once per day
**Cycle 2 onwards: 400 mg PO once per day
42-day cycles until plateau phase
====Subsequent treatment====
*Thalidomide maintenance
===Regimen variant #6, 1.25/5/200===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Wijermans et al. 2010 (HOVON 49)	2002-2007 	Phase 3 (E-esc)	MP 	Might have longer OS (secondary endpoint)Median OS: 40 vs 31 moLonger EFS (primary endpoint)Median EFS: 13 vs 9 mo(HR not reported, p<0.001)
Note: This regimen was intended for patients with previously untreated MM older than age 65 years.
====Chemotherapy====
*Melphalan (Alkeran) as follows:
**Cycles 1 to 8: 0.25 mg/kg PO once per day on days 1 to 5
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycles 1 to 8: 1 mg/kg PO once per day on days 1 to 5
====Targeted therapy====
*Thalidomide (Thalomid) 200 mg PO once per day 
====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."
*During induction therapy, low molecular weight heparin use recommended with Nadroparin (Fraxiparine) 2,850 units anti-Xa (for patients greater than 90 kg, dose of 5,700 units anti-Xa)
28-day cycle for 9 cycles
====Subsequent treatment====
*Thalidomide maintenance
===Regimen variant #7, 0.8/8/100===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hulin et al. 2009 (IFM 01/01)	2002-2006 	Phase 3 (E-esc)	MP 	Seems to have longer OS (primary endpoint)Median OS: 44 vs 29.1 mo(HR 0.68, 95% CI 0.48-0.96)
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. Note that 95% CI are not reported in the text and are calculated from P value and HR point estimate, assuming Wald P value.
====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
====Targeted therapy====
*Thalidomide (Thalomid) 100 mg PO once per day 
42-day cycle for 12 cycles
===Regimen variant #8, 1/8/400===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Facon et al. 2007 (IFM 99-06)	2000-2005 	Phase 3 (E-esc)	1. MP 	Longer OS (primary endpoint)Median OS: 51.6 vs 33.2 mo(HR 0.59, 95% CI 0.46-0.81)
Facon et al. 2007 (IFM 99-06)	2000-2005 	Phase 3 (E-esc)	2. MEL100 	Seems to have longer OS (primary endpoint)Median OS: 51.6 vs 38.3 mo(HR 0.69, 95% CI 0.49-0.96)
Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 75 years. Thalidomide dose was increased only if the prior dose was tolerated.
====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
====Targeted therapy====
*Thalidomide (Thalomid) 200 mg PO once per day, increased as tolerated after 4 weeks on therapy to maximum dose of 400 mg once per day
42-day cycle for 12 cycles
===Regimen variant #9, 28/280/100===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Palumbo et al. 2006 (GISMM2001-A)	2002-2005 	Phase 3 (E-esc)	MP 	Seems to have longer PFS1 (secondary endpoint)Median PFS: 21.8 vs 14.5 mo(HR 0.63, 95% CI 0.48-0.81)Longer EFS (primary endpoint)EFS24: 54% vs 27%(HR 0.51, 95% CI 0.35-0.75)
1Reported efficacy is based on the 2008 update.
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
====Targeted therapy====
*Thalidomide (Thalomid) 100 mg PO once per day
====Supportive therapy====
*Enoxaparin (Lovenox) as follows:
**Cycles 1 to 4: 40 mg SC once per day
28-day cycle for 6 cycles
====Subsequent treatment====
*Thalidomide maintenance
===References===
# GISMM2001-A: Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, Cangialosi C, Grasso M, Rossini F, Galli M, Catalano L, Zamagni E, Petrucci MT, De Stefano V, Ceccarelli M, Ambrosini MT, Avonto I, Falco P, Ciccone G, Liberati AM, Musto P, Boccadoro M; Italian Multiple Myeloma Network. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006 Mar 11;367(9513):825-31. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00232934
## Update: Palumbo A, Bringhen S, Liberati AM, Caravita T, Falcone A, Callea V, Montanaro M, Ria R, Capaldi A, Zambello R, Benevolo G, Derudas D, Dore F, Cavallo F, Gay F, Falco P, Ciccone G, Musto P, Cavo M, Boccadoro M. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008 Oct 15;112(8):3107-14. Epub 2008 May 27. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# IFM 99-06: Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B, Renaud M, Harousseau JL, Guillerm G, Chaleteix C, Dib M, Voillat L, Maisonneuve H, Troncy J, Dorvaux V, Monconduit M, Martin C, Casassus P, Jaubert J, Jardel H, Doyen C, Kolb B, Anglaret B, Grosbois B, Yakoub-Agha I, Mathiot C, Avet-Loiseau H; Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007 Oct 6;370(9594):1209-18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC content property of HemOnc.org NCT00367185
# IFM 01/01: Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C, Dib M, Guillerm G, Salles B, Eschard JP, Lenain P, Casassus P, Azaïs I, Decaux O, Garderet L, Mathiot C, Fontan J, Lafon I, Virion JM, Moreau P. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009 Aug 1;27(22):3664-70. Epub 2009 May 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00644306
# NMSG12: Waage A, Gimsing P, Fayers P, Abildgaard N, Ahlberg L, Björkstrand B, Carlson K, Dahl IM, Forsberg K, Gulbrandsen N, Haukås E, Hjertner O, Hjorth M, Karlsson T, Knudsen LM, Nielsen JL, Linder O, Mellqvist UH, Nesthus I, Rolke J, Strandberg M, Sørbø JH, Wisløff F, Juliusson G, Turesson I; Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010 Sep 2;116(9):1405-12. Epub 2010 May 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00218855
# HOVON 49: Wijermans P, Schaafsma M, Termorshuizen F, Ammerlaan R, Wittebol S, Sinnige H, Zweegman S, van Marwijk Kooy M, van der Griend R, Lokhorst H, Sonneveld P; Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010 Jul 1;28(19):3160-6. Epub 2010 Jun 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN90692740
# TMSG-2005-001: Beksac M, Haznedar R, Firatli-Tuglular T, Ozdogu H, Aydogdu I, Konuk N, Sucak G, Kaygusuz I, Karakus S, Kaya E, Ali R, Gulbas Z, Ozet G, Goker H, Undar L. Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011 Jan;86(1):16-22. Epub 2010 Nov 22. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00934154
# Meta-analysis: Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R, Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T; Nordic Myeloma Study Group; Italian Multiple Myeloma Network; Turkish Myeloma Study Group; Hemato-Oncologie voor Volwassenen Nederland; Intergroupe Francophone du Myélome; European Myeloma Network. Thalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685 individual patient data from 6 randomized clinical trials. Blood. 2011 Aug 4;118(5):1239-47. Epub 2011 Jun 13. link to original article EuroPMC
# FIRSTMM: Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis N, Banos A, Tiab M, Delforge M, Cavenagh J, Geraldes C, Lee JJ, Chen C, Oriol A, de la Rubia J, Qiu L, White DJ, Binder D, Anderson K, Fermand JP, Moreau P, Attal M, Knight R, Chen G, Van Oostendorp J, Jacques C, Ervin-Haynes A, Avet-Loiseau H, Hulin C, Facon T; FIRST Trial Team. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014 Sep 4;371(10):906-17. link to original article link to supplemental appendix dosing details in manuscript have been reviewed by our editors EuroPMC NCT00689936
## Update: Hulin C, Belch A, Shustik C, Petrucci MT, Dührsen U, Lu J, Song K, Rodon P, Pégourié B, Garderet L, Hunter H, Azais I, Eek R, Gisslinger H, Macro M, Dakhil S, Goncalves C, LeBlanc R, Romeril K, Royer B, Doyen C, Leleu X, Offner F, Leupin N, Houck V, Chen G, Ervin-Haynes A, Dimopoulos MA, Facon T. Updated outcomes and impact of age with lenalidomide and low-dose dexamethasone or melphalan, prednisone, and thalidomide in the randomized, phase III FIRST trial. J Clin Oncol. 2016 Oct;34(30):3609-17. Epub 2016 Jun 20. link to original article EuroPMC
## Update: Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M, Pinto A, Weisel K, Ludwig H, Bahlis NJ, Banos A, Tiab M, Delforge M, Cavenagh JD, Geraldes C, Lee JJ, Chen C, Oriol A, De La Rubia J, White D, Binder D, Lu J, Anderson KC, Moreau P, Attal M, Perrot A, Arnulf B, Qiu L, Roussel M, Boyle E, Manier S, Mohty M, Avet-Loiseau H, Leleu X, Ervin-Haynes A, Chen G, Houck V, Benboubker L, Hulin C. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018 Jan 18;131(3):301-310. Epub 2017 Nov 17. link to original article link to PMC article EuroPMC
# ECOG E1A06: Stewart AK, Jacobus S, Fonseca R, Weiss M, Callander NS, Chanan-Khan AA, Rajkumar SV. Melphalan, prednisone, and thalidomide vs melphalan, prednisone, and lenalidomide (ECOG E1A06) in untreated multiple myeloma. Blood. 2015 Sep 10;126(11):1294-301. Epub 2015 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00602641
# HOVON87/NMSG18: Zweegman S, van der Holt B, Mellqvist UH, Salomo M, Bos GM, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden AW, Deenik W, Gruber A, Coenen JL, Plesner T, Klein SK, Tanis BC, Szatkowski DL, Brouwer RE, Westerman M, Leys MR, Sinnige HA, Haukås E, van der Hem KG, Durian MF, Mattijssen EV, van de Donk NW, Stevens-Kroef MJ, Sonneveld P, Waage A. Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma. Blood. 2016 Mar 3;127(9):1109-16. Epub 2016 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2007-004007-34
##HRQoL analysis: Nielsen LK, Stege C, Lissenberg-Witte B, van der Holt B, Mellqvist UH, Salomo M, Bos G, Levin MD, Visser-Wisselaar H, Hansson M, van der Velden A, Deenik W, Coenen J, Hinge M, Klein S, Tanis B, Szatkowski D, Brouwer R, Westerman M, Leys R, Sinnige H, Haukås E, van der Hem K, Durian M, Gimsing P, van de Donk N, Sonneveld P, Waage A, Abildgaard N, Zweegman S. Health-related quality of life in transplant ineligible newly diagnosed multiple myeloma patients treated with either thalidomide or lenalidomide-based regimen until progression: a prospective, open-label, multicenter, randomized, phase 3 study. Haematologica. 2020 Jun;105(6):1650-1659. Epub 2019 Sep 12. link to original article link to PMC article EuroPMC
==PAD==
PAD: PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
PAd: PS-341 (Bortezomib), Adriamycin (Doxorubicin), low-dose dexamethasone
Note that this regimen is sometimes called VAD but this can create a lot of confusion with the "original" VAD which uses Vincristine.
VAD: Velcade (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
BDD: Bortezomib, Doxorubicin, Dexamethasone
===Regimen variant #1, 1/9/40, IV bortezomib===
Study 	Dates of enrollment	Evidence
Ludwig et al. 2010a	2006-2008 	Phase 2
Note: This is not specifically a first-line regimen but most patients enrolled on the phase 2 trial were untreated (50 out of 68). The route of bortezomib was not clearly described in the manuscript but has been confirmed with the authors.
====Targeted therapy====
*Bortezomib (Velcade) 1 mg/m2 IV once per day on days 1, 4, 8, 11
**Patients without grade 3 or 4 toxicity during the first two cycles could have bortezomib dose increased to 1.3 mg/m2 (route not specified) once per day on days 1, 4, 8, 11
====Chemotherapy====
*Doxorubicin (Adriamycin) 9 mg/m2 IV once per day on days 1 & 4
**Patients without grade 3 or 4 toxicity during the first two cycles could have number of doxorubicin doses increased to 9 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1, 4, 8, 11
21-day cycle for up to 8 cycles
===Regimen variant #2, 1.3/9/20, SC bortezomib ("PAd")===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Mai et al. 2015 (GMMG-MM5)	2010-2012 	Phase 3 (E-switch-ic)	VCD 	Non-inferior VGPR or better rate (primary endpoint)
Note: This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
====Chemotherapy====
*Doxorubicin (Adriamycin) 9 mg/m2 IV 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, 17 to 20
====Supportive therapy====
*Cotrimoxazole (dose not specified)
*Acyclovir (Zovirax) (dose not specified)
*Bisphosphonate IV every 4 weeks
28-day cycle for 3 cycles
====Subsequent treatment====
*High-dose melphalan & autologous hematopoietic cell transplant consolidation
===Regimen variant #3, 1.3/9/40 x 3, IV bortezomib===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Sonneveld et al. 2012 (HOVON-65)	2005-2008 	Phase 3 (E-switch-ooc)	VAD 	Longer PFS1 (primary endpoint)Median PFS: 35 vs 28 mo(HR 0.75, 95% CI 0.62-0.90)
Sonneveld et al. 2012 (GMMG-HD4)	2005-2008 	Phase 3 (E-switch-ooc)	VAD 	Longer PFS1 (primary endpoint)Median PFS: 35 vs 28 mo(HR 0.75, 95% CI 0.62-0.90)
1In the initial publication, this arm seemed to have an overall survival advantage; this was no longer present in the updated report of 2017.
Note: This regimen was intended for patients 18 to 65 years of age with newly diagnosed MM, Durie-Salmon stage II to III, WHO performance status 0 to 2, or WHO 3 when caused by MM. Stem cells collected 4 to 6 weeks after induction therapy. HOVON-65/GMMG-HD4 was a single phase 3 RCT but the consolidation was different by group, so is reported here as 2 distinct trials.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Chemotherapy====
*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====
(described in the appendix of Sonneveld et al. 2012):
*One of the following bisphosphonates recommended:
**Pamidronate (Aredia) 90 mg IV once every 4 to 6 weeks x at least 2 years
**Zoledronic acid (Zometa) 4 mg IV once every 4 to 6 weeks x at least 2 years
**Ibandronate (Boniva) 6 mg IV once every 4 to 6 weeks x at least 2 years
*"Prophylactic antibiotics" (no further specifics) during induction therapy
*Erythropoietin and pain medications at physician discretion
*One of the following for Herpes zoster prophylaxis throughout bortezomib induction:
**Acyclovir (Zovirax) 800 mg/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 high-dose melphalan & autologous hematopoietic cell transplant consolidation
*GMMG-HD4: Tandem high-dose melphalan & autologous hematopoietic cell transplant consolidation
===Regimen variant #4, 1.3/9/40 x 4, IV bortezomib===
Study 	Dates of enrollment	Evidence
Oakervee et al. 2005	Not reported 	Phase 2, fewer than 20 pts
Note: While this was reported as a phase 2, it was also a dose-finding study; only 14 patients were treated at the dose here.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11
====Chemotherapy====
*Doxorubicin (Adriamycin) 9 mg/m2 IV once per day on days 1 to 4
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18 
**Cycles 2 to 4: 40 mg PO once per day on days 1 to 4
21-day cycle for 4 cycles
====Subsequent treatment====
*Cyclophosphamide & G-CSF stem cell mobilization], then high-dose melphalan & autologous hematopoietic cell transplant consolidation
===References===
# Oakervee HE, Popat R, Curry N, Smith P, Morris C, Drake M, Agrawal S, Stec J, Schenkein D, Esseltine DL, Cavenagh JD. PAD combination therapy (PS-341/bortezomib, doxorubicin and dexamethasone) for previously untreated patients with multiple myeloma. Br J Haematol. 2005 Jun;129(6):755-62. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F, Autzinger EM, Thaler J, Gisslinger H, Lang A, Egyed M, Womastek I, Zojer N. Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study. J Clin Oncol. 2010 Oct 20;28(30):4635-41. Epub 2010 Sep 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00401804
# HOVON-65: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN64455289
## Subgroup analysis: Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. link to original article EuroPMC
## Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article EuroPMC
# GMMG-HD4: Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012 Aug 20;30(24):2946-55. Epub 2012 Jul 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN64455289
## Subgroup analysis: Neben K, Lokhorst HM, Jauch A, Bertsch U, Hielscher T, van der Holt B, Salwender H, Blau IW, Weisel K, Pfreundschuh M, Scheid C, Dührsen U, Lindemann W, Schmidt-Wolf IG, Peter N, Teschendorf C, Martin H, Haenel M, Derigs HG, Raab MS, Ho AD, van de Velde H, Hose D, Sonneveld P, Goldschmidt H. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012 Jan 26;119(4):940-8. Epub 2011 Dec 8. link to original article EuroPMC
## Update: Goldschmidt H, Lokhorst HM, Mai EK, van der Holt B, Blau IW, Zweegman S, Weisel KC, Vellenga E, Pfreundschuh M, Kersten MJ, Scheid C, Croockewit S, Raymakers R, Hose D, Potamianou A, Jauch A, Hillengass J, Stevens-Kroef M, Raab MS, Broijl A, Lindemann HW, Bos GMJ, Brossart P, van Marwijk Kooy M, Ypma P, Duehrsen U, Schaafsma RM, Bertsch U, Hielscher T, Jarari L, Salwender HJ, Sonneveld P. Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018 Feb;32(2):383-390. Epub 2017 Jul 4. link to original article EuroPMC
# GMMG-MM5: Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2010-019173-16
## Subgroup analysis: Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Weisel K, Duerig J, Goldschmidt H. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015 Jul;100(7):964-9. Epub 2015 Apr 3. link to original article link to PMC article EuroPMC
## Update: Goldschmidt H, Mai EK, Dürig J, Scheid C, Weisel KC, Kunz C, Bertsch U, Hielscher T, Merz M, Munder M, Lindemann HW, Hügle-Dörr B, Tichy D, Giesen N, Hose D, Seckinger A, Huhn S, Luntz S, Jauch A, Elmaagacli A, Rabold B, Fuhrmann S, Brossart P, Goerner M, Bernhard H, Hoffmann M, Hillengass J, Raab MS, Blau IW, Hänel M, Salwender HJ; German-speaking Myeloma Multicenter Group (GMMG). Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020 Jul;34(7):1853-1865. Epub 2020 Feb 7. link to original article EuroPMC
# SYSUCC-MM-308: NCT02362165
==PAD (Pegylated liposomal doxorubicin substituted)==
PAD doxil: PS-341 (Bortezomib), pegylated liposomal Adriamycin (Doxorubicin), Dexamethasone
DVD: Doxil (Pegylated liposomal doxorubicin), Velcade (Bortezomib), Dexamethasone
VDD: Velcade (Bortezomib), Doxil (Pegylated liposomal doxorubicin), Dexamethasone
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Berenson et al. 2011 (DOXILMMY2010)	2008-2010 	Phase 2
====Chemotherapy====
*Pegylated liposomal doxorubicin (Doxil) 5 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV once per day on days 1, 4, 8, 11
====Targeted therapy====
*Bortezomib (Velcade) 1 mg/m2 IV once per day on days 1, 4, 8, 11
28-day cycle for up to 8 cycles
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Palumbo et al. 2010	2005-2007 	Phase 2
====Chemotherapy====
*Pegylated liposomal doxorubicin (Doxil) 30 mg/m2 IV once on day 4
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycle 1: 40 mg PO once per day on days 1 to 4, 8 to 11, 15 to 18 
**Cycles 2 to 4: 40 mg PO once per day on days 1 to 4
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Supportive therapy====
*Acyclovir (Zovirax) recommended during bortezomib therapy
21-day cycle for 4 cycles
====Subsequent treatment====
*Tandem MEL-100, then auto HSCT consolidation
===Regimen variant #3===
Study 	Dates of enrollment	Evidence
Jakubowiak et al. 2009	2005-2007 	Phase 2
====Chemotherapy====
*Pegylated liposomal doxorubicin (Doxil) 30 mg/m2 IV once on day 4
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycle 1: 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12 
**Cycles 2 to 6: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Supportive therapy====
*One of the following, for DVT prophylaxis:
**Low-molecular weight heparin 40 mg SC once per day
**Aspirin 81 mg PO once per day
*VZV prophylaxis: Acyclovir (Zovirax) 400 mg PO twice per day
21-day cycle for 6 cycles
===References===
# Jakubowiak AJ, Kendall T, Al-Zoubi A, Khaled Y, Mineishi S, Ahmed A, Campagnaro E, Brozo C, Braun T, Talpaz M, Kaminski MS. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009 Oct 20;27(30):5015-22. Epub 2009 Sep 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Dytfeld D, Griffith KA, Friedman J, Lebovic D, Harvey C, Kaminski MS, Jakubowiak AJ. Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. Leuk Lymphoma. 2011 Jul;52(7):1271-80. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Palumbo A, Gay F, Falco P, Crippa C, Montefusco V, Patriarca F, Rossini F, Caltagirone S, Benevolo G, Pescosta N, Guglielmelli T, Bringhen S, Offidani M, Giuliani N, Petrucci MT, Musto P, Liberati AM, Rossi G, Corradini P, Boccadoro M. Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. J Clin Oncol. 2010 Feb 10;28(5):800-7. Epub 2010 Jan 4. Erratum in: J Clin Oncol. 2010 May 1;28(13):2314. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2005-004714-32
## Update: Gay F, Magarotto V, Crippa C, Pescosta N, Guglielmelli T, Cavallo F, Pezzatti S, Ferrari S, Liberati AM, Oliva S, Patriarca F, Offidani M, Omedé P, Montefusco V, Petrucci MT, Giuliani N, Passera R, Pietrantuono G, Boccadoro M, Corradini P, Palumbo A. Bortezomib induction, reduced-intensity transplantation, and lenalidomide consolidation-maintenance for myeloma: updated results. Blood. 2013 Aug 22;122(8):1376-83. Epub 2013 Jun 17. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# DOXILMMY2010: Berenson JR, Yellin O, Chen CS, Patel R, Bessudo A, Boccia RV, Yang HH, Vescio R, Yung E, Mapes R, Eades B, Hilger JD, Wirtschafter E, Hilger J, Nassir Y, Swift RA. A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol. 2011 Dec;155(5):580-7. Epub 2011 Sep 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00742404
==RVD==
RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone
===Synopsis===
Induction therapy prior to autologous stem cell transplantation (ASCT) has evolved dramatically from early days, to its current form of lenalidomide, bortezomib, and dexamethasone (RVD). Both lenalidomide and bortezomib in combination with low-dose dexamethasone, demonstrated promising activity in relapsed/refractory multiple myeloma, before being studied in newly-diagnosed patients.
The most relevant studies that have informed clinical practice have demonstrated conclusively that the combination of an immunomodulatory agent (IMiD) and proteasome inhibitor (PI) are most efficacious for disease control and long term outcomes. Intergroup trial SWOG S0777 was a randomized study comparing RVD to Rd for patients with newly diagnosed multiple myeloma, without intention for ASCT (Durie B et al, Lancet 2017 Feb 4). This trial showed a median progression-free survival (PFS) of 75 months for the RVD arm, as compared with 64 months for the Rd arm. The IFM 2013-04, next, compared outcomes with an IMiD/PI combination induction (bortezomib, thalidomide, dexamethasone – VTD) with the standard at the time, bortezomib, cyclophosphamide and dexamethasone (VCD) (Moreau P et al Blood 2016 May 26). Responses to VTD were superior to those for VCD, including rates of CR (19% vs 6%), thus establishing the IMiD and PI combination as the preferred induction regimen. As of 2018, we lack randomized data regarding the addition of daratumumab to RVD vs RVD alone, and also whether carfilzomib, lenalidomide, and dexamethasone (KRd) is superior to RVD, though both of these questions are being examined in ongoing clinical trials.
Most variation in this protocol is based on whether it is intended as induction prior to transplant or whether it is part of a transplant-ineligible approach. For the former, 3 cycles are usually given; for the latter, up to 8 cycles are given before transition to maintenance. There is also some variation in how the steroid component is given. To our knowledge, none of the major published trials have used SC bortezomib, although this has been common practice in the clinic since 2010.
===Regimen variant #1, 3 cycles, bi-weekly dexamethasone===
Study 	Dates of enrollment	Evidence
Attal et al. 2017 (IFM 2009)	2010-2012 	Non-randomized part of phase 3 RCT
Note: This regimen is intended for patients 65 years of age or younger with symptomatic, measurable, newly diagnosed multiple myeloma.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycle for 3 cycles
====Subsequent treatment====
*High-dose melphalan, then auto HSCT versus RVD consolidation
===Regimen variant #2, 3 cycles, weekly dexamethasone===
Study 	Dates of enrollment	Evidence
Roussel et al. 2014 (IFM 2008)	2009 	Phase 2
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
====Supportive therapy====
*Low–molecular weight heparin (LMWH)
*Antiviral therapy with example valacyclovir given, for herpes zoster prevention
*Antibiotic prophylaxis with example amoxicillin given, for bacterial infections 
21-day cycle for 3 cycles
====Subsequent treatment====
*High-dose melphalan and autologous hematopoietic cell transplant consolidation
===Regimen variant #3, 4 cycles variant #1===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Mai et al. 2024 (GMMG-HD6)	2015-06-29 to 2017-09-11	Phase 3 (C)	Elo-RVd 	Did not meet primary endpoint of PFS
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 & 2: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12, 15
**Cycles 3 & 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycle for 4 cycles
====Subsequent treatment====
*Melphalan, then auto HSCT, then RVd consolidation x 2 versus Elo-RVd consolidation x 2
===Regimen variant #4, 4 cycles variant #2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Facon et al. 2024 (IMROZ)	2017-12 to 2019-03 	Phase 3 (C)	Isa-RVd 	Shorter PFSPFS60: 45.2% vs 63.2%(HR 1.67, 98.5% CI 1.14-2.44)
Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 80 or otherwise ineligible for stem cell transplant.
====Targeted therapy====
*Lenalidomide (Revlimid) by the following laboratory-based criteria:
**eGFR 60 mL/min/1.73m2 or more: 25 mg PO once per day on days 1 to 14, 22 to 35
**eGFR 30 up to 60 mL/min/1.73m2: 10 mg PO once per day on days 1 to 14, 22 to 35
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 75 years old: 20 mg PO or IV once per day on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33
**75 years old or older: 20 mg PO or IV once per day on days 1, 4, 8, 11, 15, 22, 25, 29, 32
42-day cycle for 4 cycles
====Subsequent treatment====
*Rd maintenance
===Regimen variant #5, 6 cycles, q4wk===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Rosiñol et al. 2019 (PETHEMA/GEM2012)	2013-2015 	Non-randomized part of phase 3 RCT	 	
Sonneveld et al. 2023 (PERSEUS) 	2019-01-19 to 2020-01-03	Phase 3 (C) 	Dara-RVD (SC daratumumab)	Shorter PFSPFS48: 67.7% vs 84.3%(HR 2.38, 95% CI 1.69-3.33)
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
====Supportive therapy====
*Low–molecular weight heparin (LMWH)
*Antiviral therapy
28-day cycle for 6 cycles
====Subsequent treatment====
*PETHEMA/GEM2012: Melphalan, then auto HSCT versus Bu/Mel, then auto HSCT consolidation
*PERSEUS: Melphalan, then auto HSCT consolidation, then Lenalidomide maintenance
===Regimen variant #6, 8 cycles, bi-weekly dexamethasone===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Durie et al. 2016 (SWOG S0777)	2008-2012 	Phase 3 (E-esc)	Rd 	Longer PFS (primary endpoint)Median PFS: 43 vs 30 mo(HR 0.71, 96% CI 0.56-0.91)Longer OS1 (secondary endpoint)Median OS: NYR vs 69 mo(HR 0.71, 96% CI 0.54-0.93)
1Reported efficacy is based on the 2020 update.
Note: This regimen is intended for patients with previously untreated multiple myeloma who were not planned for immediate autologous stem-cell transplant.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycle for 8 cycles
====Subsequent treatment====
*Rd maintenance
===Regimen variant #7, 8 cycles, weekly dexamethasone===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (C)	1. VDC 	No formal comparison
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (C)	2. VDC; modified	No formal comparison
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (C)	3. VDCR 	No formal comparison
Note: This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
21-day cycle for 8 cycles
====Subsequent treatment====
*Bortezomib consolidation
===Regimen variant #8, 8 cycles, tapered bi-weekly dexamethasone===
Study 	Dates of enrollment	Evidence
Richardson et al. 2010 (DFCI 06-150)	2006-2008 	Phase 1/2
Note: This is the MTD level "4M" described in the manuscript.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
**Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
====Supportive therapy====
*Aspirin 81 mg or 325 mg PO once per day 
*Antiviral therapy, such as Acyclovir (Zovirax) 400 mg PO once per day 
*Bisphosphonate
21-day cycle for 8 cycles
====Subsequent treatment====
*DFCI 06-150, patients who responded and tolerated therapy could optionally proceed to: RVD maintenance
===Regimen variant #9, 12 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kumar et al. 2020 (ENDURANCE)	2013-2019 	Phase 3 (C)	KRd 	Did not meet primary endpoint of PFSMedian PFS: 34.4 vs 34.6 mo(HR 0.96, 95% CI 0.76-1.20)
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) as follows:
**Cycles 1 to 8: 1.3 mg/m2 IV or SC once per day on days 1, 4, 8, 11
**Cycles 9 to 12: 1.3 mg/m2 IV or SC once per day on days 1 & 8
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
**Cycles 5 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
**Cycles 9 to 12: 10 mg PO once per day on days 1, 2, 8, 9
21-day cycle for 12 cycles
====Subsequent treatment====
*Lenalidomide x 2 y versus indefinite Lenalidomide maintenance
===References===
# DFCI 06-150: Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS, Avigan DE, Xie W, Ghobrial IM, Schlossman RL, Mazumder A, Munshi NC, Vesole DH, Joyce R, Kaufman JL, Doss D, Warren DL, Lunde LE, Kaster S, Delaney C, Hideshima T, Mitsiades CS, Knight R, Esseltine DL, Anderson KC. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00378105
# EVOLUTION: Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00507442
# IFM 2008: Roussel M, Lauwers-Cances V, Robillard N, Hulin C, Leleu X, Benboubker L, Marit G, Moreau P, Pegourie B, Caillot D, Fruchart C, Stoppa AM, Gentil C, Wuilleme S, Huynh A, Hebraud B, Corre J, Chretien ML, Facon T, Avet-Loiseau H, Attal M. Front-line transplantation program with lenalidomide, bortezomib, and dexamethasone combination as induction and consolidation followed by lenalidomide maintenance in patients with multiple myeloma: a phase II study by the Intergroupe Francophone du Myélome. J Clin Oncol. 2014 Sep 1;32(25):2712-7. Epub 2014 Jul 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01206205
# SWOG S0777: Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, Thakuri M, Reu F, Reynolds CM, Sexton R, Orlowski RZ, Barlogie B, Dispenzieri A. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017 Feb 4;389(10068):519-527. Epub 2016 Dec 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00644228
##Update: Durie BGM, Hoering A, Sexton R, Abidi MH, Epstein J, Rajkumar SV, Dispenzieri A, Kahanic SP, Thakuri MC, Reu FJ, Reynolds CM, Orlowski RZ, Barlogie B. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J. 2020 May 11;10(5):53. link to original article link to PMC article EuroPMC
# IFM 2009: Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, Arnulf B, Macro M, Belhadj K, Garderet L, Roussel M, Payen C, Mathiot C, Fermand JP, Meuleman N, Rollet S, Maglio ME, Zeytoonjian AA, Weller EA, Munshi N, Anderson KC, Richardson PG, Facon T, Avet-Loiseau H, Harousseau JL, Moreau P; IFM. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017 Apr 6;376(14):1311-1320. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01191060
# PETHEMA/GEM2012: Rosiñol L, Oriol A, Rios R, Sureda A, Blanchard MJ, Hernández MT, Martínez-Martínez R, Moraleda JM, Jarque I, Bargay J, Gironella M, de Arriba F, Palomera L, González-Montes Y, Martí JM, Krsnik I, Arguiñano JM, González ME, González AP, Casado LF, López-Anglada L, Paiva B, Mateos MV, San Miguel JF, Lahuerta JJ, Bladé J. Bortezomib, lenalidomide, and dexamethasone as induction therapy prior to autologous transplant in multiple myeloma. Blood. 2019 Oct 17;134(16):1337-1345. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01916252
# ENDURANCE: Kumar SK, Jacobus SJ, Cohen AD, Weiss M, Callander N, Singh AK, Parker TL, Menter A, Yang X, Parsons B, Kumar P, Kapoor P, Rosenberg A, Zonder JA, Faber E Jr, Lonial S, Anderson KC, Richardson PG, Orlowski RZ, Wagner LI, Rajkumar SV. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020 Oct;21(10):1317-1330. Epub 2020 Aug 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01863550
# PERSEUS: Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, Hulin C, Antonioli E, Leleu X, Mangiacavalli S, Perrot A, Cavo M, Belotti A, Broijl A, Gay F, Mina R, Nijhof IS, van de Donk NWCJ, Katodritou E, Schjesvold F, Sureda Balari A, Rosiñol L, Delforge M, Roeloffzen W, Silzle T, Vangsted A, Einsele H, Spencer A, Hajek R, Jurczyszyn A, Lonergan S, Ahmadi T, Liu Y, Wang J, Vieyra D, van Brummelen EMJ, Vanquickelberghe V, Sitthi-Amorn A, de Boer CJ, Carson R, Rodriguez-Otero P, Bladé J, Moreau P; PERSEUS Trial Investigators. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Jan 25;390(4):301-313. Epub 2023 Dec 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03710603
# GMMG-HD6: Mai EK, Goldschmid H, Miah K, Bertsch U, Besemer B, Hänel M, Krzykalla J, Fenk R, Schlenzka J, Munder M, Dürig J, Blau IW, Huhn S, Hose D, Jauch A, Kunz C, Mann C, Weinhold N, Scheid C, Schroers R, von Metzler I, Schieferdecker A, Thomalla J, Reimer P, Mahlberg R, Graeven U, Kremers S, Martens UM, Kunz C, Hensel M, Benner A, Seidel-Glätzer A, Weisel KC, Raab MS, Salwender HJ; German-speaking Myeloma Multicenter Group (GMMG) HD6 investigators. Elotuzumab, lenalidomide, bortezomib, dexamethasone, and autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GMMG-HD6): results from a randomised, phase 3 trial. Lancet Haematol. 2024 Feb;11(2):e101-e113. Erratum in: Lancet Haematol. 2024 Mar;11(3):e181. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02495922
#IMROZ: Facon T, Dimopoulos MA, Leleu XP, Beksac M, Pour L, Hájek R, Liu Z, Minarik J, Moreau P, Romejko-Jarosinska J, Spicka I, Vorobyev VI, Besemer B, Ishida T, Janowski W, Kalayoglu-Besisik S, Parmar G, Robak P, Zamagni E, Goldschmidt H, Martin TG, Manier S, Mohty M, Oprea C, Brégeault MF, Macé S, Berthou C, Bregman D, Klippel Z, Orlowski RZ; IMROZ Study Group. Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Oct 31;391(17):1597-1609. Epub 2024 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03319667
# CARTITUDE-5: NCT04923893
# CR108529: NCT03652064
# COBRA: NCT03729804
# DSMM XIV: NCT01685814
# GMMG HD7: NCT03617731
==TAD (Thalidomide)==
TAD: Thalidomide, Adriamycin (Doxorubicin), Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lokhorst et al. 2009 (HOVON-50)	2001-2005 	Phase 3 (E-switch-ooc)	See link 	See link
====Targeted therapy====
*Thalidomide (Thalomid) 200 to 400 mg PO once per day
====Chemotherapy====
*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
28-day cycle for 3 cycles
====Subsequent treatment====
*CAD & G-CSF stem-cell mobilization
===References===
# 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; Dutch-Belgian Hemato-Oncology Group. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00028886
## Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article EuroPMC
==VDC==
VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VDC-mod: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide (modified dose)
VCD: Velcade (Bortezomib), Cyclophosphamide, Dexamethasone
CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Moreau et al. 2016 (IFM 2013-04)	2013-2015 	Phase 3 (E-switch-ooc)	VTD 	Seems to have lower ORR (secondary endpoint)
Note: This regimen was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours).
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 PO once per day on days 1, 8, 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
21-day cycle for 4 cycles
====Subsequent treatment====
*Autologous hematopoietic cell transplant consolidation, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center
===Regimen variant #2, "VCD"===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Mai et al. 2015 (GMMG-MM5)	2010-2012 	Phase 3 (E-switch-ic)	PAD 	Non-inferior VGPR or better rate (primary endpoint)
Note: This regimen was intended for patients 18 to 70 years of age with newly diagnosed MM who required systemic chemotherapy based on the CRAB criteria. Note that the bortezomib route was changed from IV to SC with a mid-protocol amendment.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 900 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
====Supportive therapy====
*Cotrimoxazole (dose not specified)
*Acyclovir (Zovirax) (dose not specified)
*Bisphosphonate IV every 4 weeks
21-day cycle for 3 cycles
====Subsequent treatment====
*High-dose melphalan & autologous hematopoietic cell transplant consolidation
===Regimen variant #3, "VDC"===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	1. VDCR 	No formal comparison
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	2. VDC; modified	No formal comparison
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	3. VDR 	No formal comparison
Note: This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. The only difference between this regimen and VDC-mod is the number of cyclophosphamide doses.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
====Supportive therapy====
*Aspirin 325 mg PO once per day 
**Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
*PCP prophylaxis recommended
*Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
*Bisphosphonates could be used "as necessary"
21-day cycle for 8 cycles
====Subsequent treatment====
*Bortezomib consolidation
===Regimen variant #4, "VDC-mod"===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	1. VDCR 	No formal comparison
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	2. VDC 	No formal comparison
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	3. VDR 	No formal comparison
Note: This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation. This arm only had 17 patients enrolled; other arms of the EVOLUTION trial all had greater than 20 patients enrolled. The only difference between this and regimen #1 is the number of cyclophosphamide doses.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1, 8, 15
====Supportive therapy====
*Aspirin 325 mg PO once per day 
**Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used instead, based on physician discretion
*PCP prophylaxis recommended
*Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
*Bisphosphonates could be used "as necessary"
21-day cycle for 8 cycles
====Subsequent treatment====
*Bortezomib consolidation
===Regimen variant #5, "CyBorD", once per week bortezomib===
Study 	Dates of enrollment	Evidence
Reeder et al. 2010	Not reported 	Phase 2
Note: This regimen was described in a letter to the editor of Blood.
====Targeted therapy====
*Bortezomib (Velcade) 1.5 mg/m2 IV once per day on days 1, 8, 15, 22
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 & 2: 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20 
**Cycles 3 & 4: 40 mg PO once per day on days 1, 8, 15, 22
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15, 22
28-day cycle for 4 cycles
===Regimen variant #6, "CyBorD"===
Study 	Dates of enrollment	Evidence
Reeder et al. 2009	Not reported 	Phase 2
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 300 mg/m2 PO once per day on days 1, 8, 15, 22
====Supportive therapy====
*Proton pump inhibitor (PPI)
*Acyclovir (Zovirax)
*Quinolone antibiotic
*Antifungal mouthwash recommended
28-day cycle for 4 to 12 cycles
===References===
# Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J, Noble B, Pirooz NA, Spong JE, Piza JG, Zepeda VH, Mikhael JR, Leis JF, Bergsagel PL, Fonseca R, Stewart AK. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009 Jul;23(7):1337-41. Epub 2009 Feb 19. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, Hentz J, Pirooz NA, Piza JG, Tiedemann R, Mikhael JR, Bergsagel PL, Leis JF, Fonseca R, Stewart AK. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010 Apr 22;115(16):3416-7. link to original letter dosing details in manuscript have been reviewed by our editors EuroPMC
# EVOLUTION: Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00507442
# Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article EuroPMC
# GMMG-MM5: Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015 Aug;29(8):1721-9. Epub 2015 Mar 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2010-019173-16
## Subgroup analysis: Merz M, Salwender H, Haenel M, Mai EK, Bertsch U, Kunz C, Hielscher T, Blau IW, Scheid C, Hose D, Seckinger A, Jauch A, Hillengass J, Raab MS, Schurich B, Munder M, Schmidt-Wolf IG, Gerecke C, Lindemann HW, Zeis M, Weisel K, Duerig J, Goldschmidt H. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015 Jul;100(7):964-9. Epub 2015 Apr 3. link to original article link to PMC article EuroPMC
## Update: Goldschmidt H, Mai EK, Dürig J, Scheid C, Weisel KC, Kunz C, Bertsch U, Hielscher T, Merz M, Munder M, Lindemann HW, Hügle-Dörr B, Tichy D, Giesen N, Hose D, Seckinger A, Huhn S, Luntz S, Jauch A, Elmaagacli A, Rabold B, Fuhrmann S, Brossart P, Goerner M, Bernhard H, Hoffmann M, Hillengass J, Raab MS, Blau IW, Hänel M, Salwender HJ; German-speaking Myeloma Multicenter Group (GMMG). Response-adapted lenalidomide maintenance in newly diagnosed myeloma: results from the phase III GMMG-MM5 trial. Leukemia. 2020 Jul;34(7):1853-1865. Epub 2020 Feb 7. link to original article EuroPMC
# IFM 2013-04: Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01971658
==VMP==
VMP: Velcade (Bortezomib), Melphalan, Prednisone
MPV: Melphalan, Prednisone, Velcade (Bortezomib)
===Regimen variant #1, 4 cycles===
Study 	Dates of enrollment	Evidence
Mateos et al. 2006	2004-2005 	Phase 1/2
Note: this was the phase 2 portion of this phase 1/2 study.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
====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 4 cycles
====Subsequent treatment====
*VMP consolidation
===Regimen variant #2, 6 cycles, bi-weekly bortezomib===
Study 	Dates of enrollment 	Evidence
Gasparetto et al. 2009	2004-08-05 to 2007-08-31	Phase 2
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Chemotherapy====
*Melphalan (Alkeran) 6 mg/m2 PO once per day on days 1 to 7, given at least 1 hour prior to bortezomib
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 7
====Supportive therapy====
*Bisphosphonates recommended
*Acyclovir (Zovirax) (dose not specified) recommended
28-day cycle for up to 6 cycles; treatment could be given beyond 6 cycles at investigator discretion
===Regimen variant #3, 6 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 5===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Mateos et al. 2010 (GEM2005)	2006-2008 	Phase 3 (C)	VTP 	Seems to have longer OS1 (secondary endpoint)Median OS: 63 vs 43 mo(HR 0.67, 95% CI 0.49-0.91)
1Reported efficacy is based on the 2014 update.
Note: This regimen was intended for patients with untreated multiple myeloma, 65 years and older.
====Targeted therapy====
*Bortezomib (Velcade) as follows:
**Cycle 1: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32 
**Cycles 2 to 5: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
====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
====Supportive therapy====
*Patients with bone disease received bisphosphonates
*Prophylactic aciclovir was recommended.
42-day course, then 35-day cycle for 5 cycles
====Subsequent treatment====
*VP versus VT maintenance
===Regimen variant #4, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Niesvizky et al. 2015 (UPFRONT)	2007-2010 	Phase 3b (E-esc)	1. Vd 	Did not meet primary endpoint of PFS
Niesvizky et al. 2015 (UPFRONT)	2007-2010 	Phase 3b (E-esc)	2. VTD 	Did not meet primary endpoint of PFS
Note: This regimen was meant for transplant ineligible patients.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Chemotherapy====
*Melphalan (Alkeran) as follows:
**Cycles 1, 3, 5, 7: 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycles 1, 3, 5, 7: 60 mg/m2 PO once per day on days 1 to 4
21-day cycle for 8 cycles
====Subsequent treatment====
*Bortezomib consolidation
===Regimen variant #5, 9 cycles, bi-weekly bortezomib x 1, then weekly bortezomib x 8===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Mateos et al. 2017 (ALCYONE)	2015-02-09 to 2016-07-14	Phase 3 (C)	Dara-VMP 	Shorter PFS (primary endpoint)PFS18: 50.2% vs 71.6%(HR 2.00, 95% CI 1.54-2.63)Shorter OS1 (secondary endpoint)OS36: 68% vs 78%(HR 1.67, 95% CI 1.25-2.17)
1Reported efficacy is based on the 2019 update.
Note: This regimen was intended for patients with newly diagnosed, documented multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older.
====Targeted therapy====
*Bortezomib (Velcade) as follows:
**Cycle 1: 1.3 mg/m2 SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
**Cycles 2 to 9: 1.3 mg/m2 SC once per day on days 1, 8, 22, 29
====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 #6, 9 cycles, bi-weekly bortezomib x 4, then weekly bortezomib x 5===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
San Miguel et al. 2008 (VISTA) 	2004-2006 	Phase 3 (E-RT-esc) 	MP 	Longer OS1 (secondary endpoint)Median OS: 56.4 vs 43.1 mo(HR 0.695, 95% CI 0.57-0.85)Longer TTP (primary endpoint)Median TTP: 24 vs 16.6 mo(HR 0.48)
Palumbo et al. 2010 (GIMEMA MM-03-05)	2006-05 to 2009-01 	Phase 3 (C) 	VMPT-VT 	Shorter PFS (primary endpoint)PFS36: 41% vs 56%(HR 1.49, 95% CI 1.11-2.00)Shorter OS2 (secondary endpoint)OS60: 51% vs 61%(HR 1.43, 95% CI 1.09-1.92)
San-Miguel et al. 2014 (CR015901) 	2009-2011 	Randomized Phase 2 (C)	VMP & Siltuximab	Did not meet primary endpoint of CR rateCR rate: 22% vs 27%
Facon et al. 2019 (CLARION) 	2013-2015 	Phase 3 (C) 	KMP 	Did not meet primary endpoint of PFSMedian PFS: 22.1 vs 22.3 mo(HR 1.10, 95% CI 0.91-1.34)
1Reported efficacy for VISTA is based on the 2012 update.
2Reported efficacy for GIMEMA MM-03-05 is based on the 2014 update.
Note: In GIMEMA MM-03-05, VISTA, and CLARION 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.
====Targeted therapy====
*Bortezomib (Velcade) as follows:
**Cycles 1 to 4: 1.3 mg/m2 IV or SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
**Cycles 5 to 9: 1.3 mg/m2 IV or SC once per day on days 1, 8, 22, 29
====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
====Supportive therapy====
*Bisphosphonates given to patients with myeloma-associated bone disease unless contraindicated (only mentioned in San Miguel et al. 2008)
42-day cycle for 9 cycles
===Regimen variant #7, 9 cycles, weekly bortezomib===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Palumbo et al. 2010 (GIMEMA MM-03-05)	2006-05 to 2009-01 	Phase 3 (C)	VMPT-VT 	Shorter PFS (primary endpoint)PFS36: 41% vs 56%(HR 1.49, 95% CI 1.11-2.00)Shorter OS1 (secondary endpoint)OS60: 51% vs 61%(HR 1.43, 95% CI 1.09-1.92)
1Reported efficacy is based on the 2014 update.
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. This dosing is the result of a mid-protocol amendment.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 8, 15, 22
====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
35-day cycle for 9 cycles
===References===
# Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Díaz-Mediavilla J, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, de Arriba F, Alegre A, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006 Oct 1;108(7):2165-72. Epub 2006 Jun 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 
## Update: Mateos MV, Hernández JM, Hernández MT, Gutiérrez NC, Palomera L, Fuertes M, Garcia-Sanchez P, Lahuerta JJ, de la Rubia J, Terol MJ, Sureda A, Bargay J, Ribas P, Alegre A, de Arriba F, Oriol A, Carrera D, García-Laraña J, García-Sanz R, Bladé J, Prósper F, Mateo G, Esseltine DL, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: updated time-to-events results and prognostic factors for time to progression. Haematologica. 2008 Apr;93(4):560-5. Epub 2008 Mar 5. link to original article EuroPMC 
# VISTA: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG; VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008 Aug 28;359(9):906-17. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00111319
## Update: Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Esseltine DL, Liu K, Cakana A, van de Velde H, San Miguel JF. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010 May 1;28(13):2259-66. Epub 2010 Apr 5. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
##HRQoL analysis: Delforge M, Dhawan R, Robinson D Jr, Meunier J, Regnault A, Esseltine DL, Cakana A, van de Velde H, Richardson PG, San Miguel JF. Health-related quality of life in elderly, newly diagnosed multiple myeloma patients treated with VMP vs MP: results from the VISTA trial. Eur J Haematol. 2012 Jul;89(1):16-27. Epub 2012 May 7. link to original article EuroPMC
## Update: San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Delforge M, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Deraedt W, Cakana A, van de Velde H, Richardson PG. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013 Feb 1;31(4):448-55. Epub 2012 Dec 10. link to original article EuroPMC 
# Gasparetto C, Gockerman JP, Diehl LF, de Castro CM, Moore JO, Long GD, Horwitz ME, Keogh G, Chute JP, Sullivan KM, Neuwirth R, Davis PH, Sutton LM, Anderson RD, Chao NJ, Rizzieri D. "Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma. Biol Blood Marrow Transplant. 2010 Jan;16(1):70-7. Epub 2009 Sep 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# GEM2005: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00443235
## Subgroup analysis: Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. link to original article EuroPMC
## Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article EuroPMC
## Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators?. Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# GIMEMA MM-03-05: Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01063179
## Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Subgroup analysis: Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. link to original article EuroPMC
## Subgroup analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article EuroPMC
## Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# CR015901: San-Miguel J, Bladé J, Shpilberg O, Grosicki S, Maloisel F, Min CK, Polo Zarzuela M, Robak T, Prasad SV, Tee Goh Y, Laubach J, Spencer A, Mateos MV, Palumbo A, Puchalski T, Reddy M, Uhlar C, Qin X, van de Velde H, Xie H, Orlowski RZ. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood. 2014 Jun 26;123(26):4136-42. Epub 2014 May 15. Erratum in: Blood. 2014 Aug 14;124(7):1201. link to original article refers to protocol in San Miguel et al. 2008 link to PMC article EuroPMC NCT00911859
# UPFRONT: Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00507416
# ALCYONE: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02195479
## Update: Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Krevvata M, Chen Y, Wang J, Kudva A, Ukropec J, Wroblewski S, Qi M, Kobos R, San-Miguel J. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-141. Epub 2019 Dec 10. link to original article EuroPMC
##HRQoL analysis: Knop S, Mateos MV, Dimopoulos MA, Suzuki K, Jakubowiak A, Doyen C, Lucio P, Nagy Z, Usenko G, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Losava G, Fujisaki T, Garg M, Wang J, Wroblewski S, Kudva A, Gries KS, Fastenau J, San-Miguel J, Cavo M. Health-related quality of life in patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation: results from the randomized phase III ALCYONE trial. BMC Cancer. 2021 Jun;21(1):659. link to original article link to EuroPMC
# CLARION: Facon T, Lee JH, Moreau P, Niesvizky R, Dimopoulos M, Hajek R, Pour L, Jurczyszyn A, Qiu L, Klippel Z, Zahlten-Kumeli A, Osman M, Paiva B, San-Miguel J. Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma. Blood. 2019 May 2;133(18):1953-1963. Epub 2019 Feb 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01818752
==VTD==
VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone
vTD: low-dose velcade (Bortezomib), Thalidomide, Dexamethasone
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Moreau et al. 2016 (IFM 2013-04) 	2013-2015 	Phase 3 (E-switch-ooc)	VCD 	Seems to have higher ORR (secondary endpoint)
Moreau et al. 2019 (CASSIOPEIA part 1)	2015-2017 	Phase 3 (C) 	Dara-VTD 	Lower sCR rate
Note: The steroid dosing in CASSIOPEIA part 1 was not clearly described in the abstract; see paper for details.
====Eligibility criteria====
*IFM 2013-04: patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours)
*CASSIOPEIA part 1: patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy with stem-cell transplantation
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 100 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
21-day cycle for 4 cycles
====Subsequent treatment====
*IFM 2013-04: Autologous hematopoietic cell transplant consolidation, with choice of conditioning regimen, whether to perform tandem transplant, and whether to give maintenance at the discretion of the treating center
*CASSIOPEIA part 1: Melphalan with auto HSCT, then VTD consolidation
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Niesvizky et al. 2015 (UPFRONT)	2007-2010 	Phase 3b (E-esc)	1. Vd 	Did not meet primary endpoint of PFS
Niesvizky et al. 2015 (UPFRONT)	2007-2010 	Phase 3b (E-esc)	2. VMP 	Did not meet primary endpoint of PFS
Note: This regimen was intended for patients with newly diagnosed, symptomatic, measurable MM requiring systemic therapy, and who were ineligible for stem-cell transplantation because of age (greater than or equal to 65 years), comorbidities, or personal preference.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
**Cycles 5 to 8: 20 mg PO once per day on days 1, 2, 4, 5
21-day cycle for 8 cycles
====Subsequent treatment====
*Bortezomib consolidation
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ludwig et al. 2012 (26866138-MMY-2043)	2007-2008 	Randomized Phase 2 (C)	VTDC 	Did not meet primary endpoint of nCR or better rateCR/nCR rate: 51% vs 44%
Note: This regimen was intended for patients aged 18 to 70 years with previously untreated, measurable MM requiring systemic therapy, who were candidates for high-dose chemotherapy and autologous hematopoietic cell transplant.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 100 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
21-day cycle for 4 cycles
====Subsequent treatment====
*26866138-MMY-2043, patients who remained eligible for transplant: High-dose melphalan with autologous hematopoietic cell transplant consolidation
*26866138-MMY-2043, transplant-ineligible patients or patients achieving CR: Optional VTD continuation x 4 (8 total cycles)
===Regimen variant #4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rosiñol et al. 2012 (GEM05/MENOS65)	2006-2009 	Phase 3 (E-esc)	1. TD 	Seems to have longer PFS (secondary endpoint)Higher CR rate (primary endpoint)
Rosiñol et al. 2012 (GEM05/MENOS65)	2006-2009 	Phase 3 (E-esc)	2. VBMCP/VBAD, then B	Seems to have longer PFS (secondary endpoint)
Note: This regimen was intended for patients with newly diagnosed and untreated symptomatic MM who were 65 years of age or younger with measurable serum and/or urine M protein.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) as follows:
**Cycle 1: 50 mg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28 
**Cycles 2 to 6: 200 mg PO once per day on days 1 to 28
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
====Supportive therapy====
*Low molecular weight heparin (LMWH) or Aspirin recommended
28-day cycle for 6 cycles
====Subsequent treatment====
*High-dose melphalan autologous hematopoietic cell transplant consolidation
===Regimen variant #5, "vTD"===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Moreau et al. 2011 (IFM 2007-02)	2008-03 to 2009-01 	Phase 3 (E-esc)	Vd 	Higher VGPR rate (secondary endpoint)Did not meet primary endpoint of CR rate after 4 cycles
Lok et al. 2014 	2011-2013 	Non-randomized 	 	
Note: IFM 2007-02 was intended for patients aged 65 years or younger with untreated symptomatic MM with measurable paraprotein in serum (greater than 1 g/dL) or urine (greater than 0.2 g/24 hours). Lok et al. 2014 uses the same dosing except that bortezomib is given SC.
====Targeted therapy====
*Bortezomib (Velcade) 1 mg/m2 IV or SC once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 100 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 & 2: 40 mg (route not specified) once per day on days 1 to 4, 9 to 12
**Cycles 3 & 4: 40 mg (route not specified) once per day on days 1 to 4
21-day cycle for 4 cycles
====Subsequent treatment====
*High-dose melphalan with autologous hematopoietic cell transplant consolidation
===Regimen variant #6===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cavo et al. 2010 (GIMEMA MM-BO2005)	2006-2008 	Phase 3 (E-esc)	TD 	Longer OS1 (secondary endpoint)Median OS: NYR vs 110 mo(HR 0.68, 95% CI 0.51-0.90)Higher CR rate/nCR rate (composite primary endpoint)
1Reported efficacy is based on the 2020 update.
Note: This regimen was intended for patients aged 18 to 65 years with previously untreated symptomatic myeloma.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) as follows:
**Cycle 1: 100 mg PO once per day on days 1 to 14, then 200 mg PO once per day on days 15 to 21
**Cycles 2 & 3: 200 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
21-day cycle for 3 cycles
====Subsequent treatment====
*Tandem MEL200 with auto HSCT consolidation, with interim Thal-Dex maintenance (see paper for details)
===Regimen variant #7===
Study 	Dates of enrollment	Evidence
Kaufman et al. 2010	2005-01 to 2007-12 	Retrospective
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 100 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 9 to 12
====Supportive therapy====
*Aspirin prophylaxis to decrease risk of DVTs
*Prophylactic "treatment with antiviral and antibiotic medications"
21-day cycle for 3 to 4 cycles
===References===
# Retrospective: Kaufman JL, Nooka A, Vrana M, Gleason C, Heffner LT, Lonial S. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer. 2010 Jul 1;116(13):3143-51. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# GIMEMA MM-BO2005: Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, Di Raimondo F, Crippa C, Zamagni E, Palumbo A, Offidani M, Corradini P, Narni F, Spadano A, Pescosta N, Deliliers GL, Ledda A, Cellini C, Caravita T, Tosi P, Baccarani M; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010 Dec 18;376(9758):2075-85. Epub 2010 Dec 9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01134484
## Update: Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L, Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood. 2012 Jul 5;120(1):9-19. Epub 2012 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Tacchetti P, Pantani L, Patriarca F, Petrucci MT, Zamagni E, Dozza L, Galli M, Di Raimondo F, Crippa C, Boccadoro M, Barbato S, Tosi P, Narni F, Montefusco V, Testoni N, Spadano A, Terragna C, Pescosta N, Marzocchi G, Cellini C, Galieni P, Ronconi S, Gobbi M, Catalano L, Lazzaro A, De Sabbata G, Cangialosi C, Ciambelli F, Musto P, Elice F, Cavo M; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto Italian Myeloma Network). Bortezomib, thalidomide, and dexamethasone followed by double autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GIMEMA-MMY-3006): long-term follow-up analysis of a randomised phase 3, open-label study. Lancet Haematol. 2020 Dec;7(12):e861-e873. link to original article EuroPMC
# IFM 2007-02: Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G, Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M, Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011 Nov 24;118(22):5752-8. Epub 2011 Aug 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00910897
# GEM05/MENOS65: Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez J, de la Rubia J, Granell M, Besalduch J, Palomera L, González Y, Etxebeste MA, Díaz-Mediavilla J, Hernández MT, de Arriba F, Gutiérrez NC, Martín-Ramos ML, Cibeira MT, Mateos MV, Martínez J, Alegre A, Lahuerta JJ, San Miguel J, Bladé J; PETHEMA; GEM. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012 Aug 3;120(8):1589-96. Epub 2012 Jul 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00461747
## Update: Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J, Granell M, Sampol M, Palomera L, González Y, Etxebeste M, Martínez-Martínez R, Hernández MT, de Arriba F, Alegre A, Cibeira M, Mateos M, Martínez-López J, Lahuerta JJ, San Miguel J, Bladé J. Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017 Sep;31(9):1922-1927. Epub 2017 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 26866138-MMY-2043: Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Ricci D, Cakana A, Enny C, Feng H, van de Velde H, Harousseau JL. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013 Jan 10;31(2):247-55. Epub 2012 Oct 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00531453
## Update: Ludwig H, Greil R, Masszi T, Spicka I, Shpilberg O, Hajek R, Dmoszynska A, Paiva B, Vidriales MB, Esteves G, Stoppa AM, Robinson D Jr, Chaturvedi S, Ataman O, Enny C, Feng H, van de Velde H, Viterbo L. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol. 2015 Nov;171(3):344-54. Epub 2015 Jul 7. link to original article link to PMC article EuroPMC
# Lok A, Mocquard J, Bourcier J, Redelsperger L, Bonnet A, Chauvin C, Thomare P, Mahe B, Touzeau C, Moreau P. Subcutaneous bortezomib incorporated into the bortezomib-thalidomide-dexamethasone regimen as part of frontline therapy in the context of autologous stem-cell transplantation for multiple myeloma. Haematologica. 2014 Mar;99(3):e33-4. Epub 2014 Feb 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# Meta-Analysis: Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R, Nagler A, Avigdor A. Bortezomib-Cyclophosphamide-Dexamethasone (VCD) versus Bortezomib-Thalidomide-Dexamethasone (VTD) -based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol. 2014 Sep;166(5):702-10. Epub 2014 May 26. link to original article EuroPMC
# UPFRONT: Niesvizky R, Flinn IW, Rifkin R, Gabrail N, Charu V, Clowney B, Essell J, Gaffar Y, Warr T, Neuwirth R, Zhu Y, Elliott J, Esseltine DL, Niculescu L, Reeves J. Community-based phase IIIB trial of three UPFRONT bortezomib-based myeloma regimens. J Clin Oncol. 2015 Nov 20;33(33):3921-9. Epub 2015 Jun 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00507416
# IFM 2013-04: Moreau P, Hulin C, Macro M, Caillot D, Chaleteix C, Roussel M, Garderet L, Royer B, Brechignac S, Tiab M, Puyade M, Escoffre M, Stoppa AM, Facon T, Pegourie B, Chaoui D, Jaccard A, Slama B, Marit G, Laribi K, Godmer P, Luycx O, Eisenmann JC, Allangba O, Dib M, Araujo C, Fontan J, Belhadj K, Wetterwald M, Dorvaux V, Fermand JP, Rodon P, Kolb B, Glaisner S, Malfuson JV, Lenain P, Biron L, Planche L, Caillon H, Avet-Loiseau H, Dejoie T, Attal M. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016 May 26;127(21):2569-74. Epub 2016 Mar 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01971658
# CASSIOPEIA part 1: Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, Béné MC, Broijl A, Caillon H, Caillot D, Corre J, Delforge M, Dejoie T, Doyen C, Facon T, Sonntag C, Fontan J, Garderet L, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Lenain P, Macro M, Mathiot C, Orsini-Piocelle F, Perrot A, Stoppa AM, van de Donk NW, Wuilleme S, Zweegman S, Kolb B, Touzeau C, Roussel M, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Fermand JP, Escoffre-Barbe M, Eveillard JR, Garidi R, Ahmadi T, Zhuang S, Chiu C, Pei L, de Boer C, Smith E, Deraedt W, Kampfenkel T, Schecter J, Vermeulen J, Avet-Loiseau H, Sonneveld P. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jul 6;394(10192):29-38. Epub 2019 Jun 3. Erratum in: Lancet. 2019 Jun 14. link to original article EuroPMC NCT02541383
##HRQoL analysis: Roussel M, Moreau P, Hebraud B, Laribi K, Jaccard A, Dib M, Slama B, Dorvaux V, Royer B, Frenzel L, Zweegman S, Klein SK, Broijl A, Jie KS, Wang J, Vanquickelberghe V, de Boer C, Kampfenkel T, Gries KS, Fastenau J, Sonneveld P. Bortezomib, thalidomide, and dexamethasone with or without daratumumab for transplantation-eligible patients with newly diagnosed multiple myeloma (CASSIOPEIA): health-related quality of life outcomes of a randomised, open-label, phase 3 trial. Lancet Haematol. 2020 Dec;7(12):e874-e883. link to original article EuroPMC
##Update: Moreau P, Hulin C, Perrot A, Arnulf B, Belhadj K, Benboubker L, Zweegman S, Caillon H, Caillot D, Avet-Loiseau H, Delforge M, Dejoie T, Facon T, Sonntag C, Fontan J, Mohty M, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Macro M, Orsini-Piocelle F, Roussel M, Schiano de Colella JM, van de Donk NW, Wuillème S, Broijl A, Touzeau C, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Offner F, Escoffre-Barbe M, Eveillard JR, Garidi R, Hua W, Wang J, Tuozzo A, de Boer C, Rowe M, Vanquickelberghe V, Carson R, Vermeulen J, Corre J, Sonneveld P; Intergroupe Francophone du Myélome, the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and the CASSIOPEIA Investigators. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024 Aug;25(8):1003-1014. Epub 2024 Jun 15. link to original article EuroPMC
#EMN18: NCT03896737
==VTP==
VTP: Velcade (Bortezomib), Thalidomide, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Mateos et al. 2010 (GEM2005)	2006-2008 	Phase 3 (E-switch-ooc)	VMP 	Seems to have shorter OS1 (secondary endpoint)Median OS: 43 vs 63 mo(HR 1.49, 95% CI 1.10-2.04)
1Reported efficacy is based on the 2014 update.
Note: This regimen was intended for patients with untreated multiple myeloma, 65 years and older.
====Targeted therapy====
*Bortezomib (Velcade) as follows:
**Cycle 1: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
**Cycles 2 to 6: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
*Thalidomide (Thalomid) as follows:
**Cycle 1: 50 mg PO once per day on days 1 to 15, then 100 mg PO once per day on days 16 to 42
**Cycles 2 to 6: 100 mg PO once per day
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
====Supportive therapy====
*Patients with bone disease received bisphosphonates
*Prophylactic aciclovir was recommended.
*Thromboprophylaxis: Aspirin or low-molecular-weight heparin
42-day course, then 35-day cycle for 5 cycles
====Subsequent treatment====
*VP versus VT maintenance
===References===
# GEM2005: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010 Oct;11(10):934-41. Epub 2010 Aug 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00443235
## Subgroup analysis: Mateos MV, Gutiérrez NC, Martín-Ramos ML, Paiva B, Montalbán MA, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Martín A, Díaz-Mediavilla J, de Arriba F, Palomera L, Hernández JM, Sureda A, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, Fernández M, García-Sanz R, Vidriales MB, Bladé J, Lahuerta JJ, San Miguel JF. Outcome according to cytogenetic abnormalities and DNA ploidy in myeloma patients receiving short induction with weekly bortezomib followed by maintenance. Blood. 2011 Oct 27;118(17):4547-53. Epub 2011 Sep 6. link to original article EuroPMC
## Update: Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Polo M, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Lahuerta JJ, Bladé J, San-Miguel JF. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012 Sep 27;120(13):2581-8. Epub 2012 Aug 13. link to original article EuroPMC
## Update: Mateos MV, Oriol A, Martínez-López J, Teruel AI, López de la Guía A, López J, Bengoechea E, Pérez M, Martínez R, Palomera L, de Arriba F, González Y, Hernández JM, Granell M, Bello JL, Bargay J, Peñalver FJ, Martín-Mateos ML, Paiva B, Montalbán MA, Bladé J, Lahuerta JJ, San-Miguel JF. Update of the GEM2005 trial comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators?. Blood. 2014 Sep 18;124(12):1887-93. Epub 2014 Aug 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=First-line therapy, quadruplets=
==CYKLONE==
CYKLONE: Cyclophosphamide, Kyprolis (Carfilzomib), ThaLidomide, DexamethasONE
===Regimen===
Study 	Dates of enrollment	Evidence
Mikhael et al. 2015 (MC0982)	2010-2013 	Phase 2
Note: The carfilzomib dose here is the MTD dose, tested in N=29 patients. The authors state that patients could proceed to autologous hematopoietic cell transplant after four cycles but do not provide criteria to undergo transplant as opposed to continuing CYKLONE.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 300 mg/m2/day PO on days 1, 8, 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg/day PO on days 1, 8, 15, 22
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
**Cycles 2 to 4 up to 12: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
*Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28
====Supportive therapy====
*Aspirin or LMWH for patients intolerant of aspirin
*Acyclovir (Zovirax) 400 mg PO twice per day
*Antibacterials (not further specified)
*250 to 500 ml of IVF, given prior to cycle 1 doses of carfilzomib and then only for patients "at risk for tumor lysis syndrome" in subsequent cycles
28-day cycle for 4 to 12 cycles (see note)
===References===
# MC0982: Mikhael JR, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, Mayo A, Nagi Reddy SK, Gano K, Dueck AC, Stewart AK. Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma. Br J Haematol. 2015 Apr;169(2):219-27. Epub 2015 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01057225
==Dara-KRd==
Dara-KRd: Daratumumab, Kyprolis (Carfilzomib), Revlimid (Lenalidomide), Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence
Landgren et al. 2021 (MANHATTAN)	2018-2019 	Non-randomized
Note: The dosing of carfilzomib in the abstract (20/56) does not reconcile with the dosing on ClinicalTrials.gov (20/36). The authors have been contacted and have clarified that the weekly dosing as replicated here is correct.
====Targeted therapy====
*Daratumumab (Darzalex) as follows:
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
**Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15
**Cycles 7 & 8: 16 mg/kg IV once on day 1
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once on day 1, then 56 mg/m2 IV once per day on days 8 & 15
**Cycles 2 to 8: 56 mg/m2 IV once per day on days 1, 8, 15
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 4: 40 mg PO or IV once per day on days 1, 8, 15, 22
**Cycles 5 to 8: 20 mg PO once per day on days 1, 8, 15, 22
**Patients older than 75 years or underweight (BMI less than 18.5) received 20 mg weekly
28-day cycle for 8 cycles
===References===
#MANHATTAN: Landgren O, Hultcrantz M, Diamond B, Lesokhin AM, Mailankody S, Hassoun H, Tan C, Shah UA, Lu SX, Salcedo M, Werner K, Rispoli J, Caple J, Sams A, Verducci D, Jones K, Concepcion I, Ciardello A, Chansakul A, Schlossman J, Tavitian E, Shekarkhand T, Harrison A, Piacentini C, Rustad EH, Yellapantula V, Maclaughlan K, Maura F, Landau HJ, Scordo M, Chung DJ, Shah G, Lahoud OB, Thoren K, Murata K, Ramanathan L, Arcila ME, Ho C, Roshal M, Dogan A, Derkach A, Giralt SA, Korde N. Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial. JAMA Oncol. 2021 Jun 1;7(6):862-868. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT03290950
#ADVANCE: NCT04268498
==Dara-RVd==
Dara-RVd: Daratumumab, Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
D-RVd: Daratumumab, Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
===Synopsis===
Introduction:
The evolution of front line therapy with Dara-RVd (daratumumab, lenalidomide, bortezomib, and dexamethasone) for multiple myeloma has progressed through several stages, involving a shift from traditional treatment approaches to the incorporation of monoclonal antibodies and immunomodulatory drugs. This summary highlights the key developments in the use of Dara-RVd as a front line therapy for multiple myeloma, supported by relevant literature.
Initial Combination Therapy:
The combination of lenalidomide, bortezomib, and dexamethasone (RVd) emerged as a standard of care for the treatment of newly diagnosed multiple myeloma patients ( Richardson et al., 2010). This regimen showed significant improvement in progression-free survival and overall survival compared to previous therapies.
Introduction of Daratumumab:
Daratumumab, a monoclonal antibody targeting CD38, demonstrated significant efficacy as a single agent in relapsed/refractory multiple myeloma ( Lonial et al., 2016). The success of daratumumab led to its incorporation into combination regimens with existing therapies.
Development of Dara-RVd:
The addition of daratumumab to the RVd regimen (Dara-RVd) was investigated in the randomized phase 2 GRIFFIN trial, which compared Dara-RVd to RVd alone in newly diagnosed multiple myeloma patients ( Voorhees et al., 2020). The trial results demonstrated improved response rates and minimal residual disease negativity for Dara-RVd, indicating its potential as a more effective front line therapy.
Conclusion:
The evolution of front line therapy with Dara-RVd for multiple myeloma has been marked by the successful integration of daratumumab with established treatment regimens, offering improved clinical outcomes for newly diagnosed patients. 
Practical Considerations
Although the GRIFFIN trial utilized bortezomib dosing on days 1, 4, 8, and 11 of a 21 day cycle, in practice, many oncologists are utilizing weekly bortezomib dosing of 1.3 - 1.5 mg/m2 SQ on days 1, 8, and 15, of a 28 day cycle. Although this has not been investigated in a randomized clinical trial, given prior prospective data such as published by O'Donnell et al , RVD-Lite, where weekly bortezomib dosing was utilized, there is some evidence that bortezomib can be given weekly in an induction context and demonstrate comparable response rates.
The draft for this synopsis was generated by a large language model and then manually edited by the page editor for accuracy and style. See this page for more information about this pilot project.
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Voorhees et al. 2020 (GRIFFIN)	2016-2018 	Randomized Phase 2 (E-esc)	RVd 	Might have higher sCR rate (primary endpoint)
Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 18-70 and eligible for stem cell transplant.
====Targeted therapy====
*Daratumumab (Darzalex) 16 mg/kg IV once per day on days 1, 8, 15
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16
21-day cycle for 4 cycles
====Subsequent treatment====
*Melphalan, then auto HSCT, then Dara-RVd consolidation
===References===
#GRIFFIN: Voorhees PM, Kaufman JL, Laubach J, Sborov DW, Reeves B, Rodriguez C, Chari A, Silbermann R, Costa LJ, Anderson LD Jr, Nathwani N, Shah N, Efebera YA, Holstein SA, Costello C, Jakubowiak A, Wildes TM, Orlowski RZ, Shain KH, Cowan AJ, Murphy S, Lutska Y, Pei H, Ukropec J, Vermeulen J, de Boer C, Hoehn D, Lin TS, Richardson PG. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020 Aug 20;136(8):936-945. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02874742
##Update: Voorhees PM, Sborov DW, Laubach J, Kaufman JL, Reeves B, Rodriguez C, Chari A, Silbermann R, Costa LJ, Anderson LD Jr, Nathwani N, Shah N, Bumma N, Efebera YA, Holstein SA, Costello C, Jakubowiak A, Wildes TM, Orlowski RZ, Shain KH, Cowan AJ, Dinner S, Pei H, Cortoos A, Patel S, Lin TS, Usmani SZ, Richardson PG. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023 Oct;10(10):e825-e837. Epub 2023 Sep 11. link to original article EuroPMC
==Dara-RVd (SC daratumumab)==
Dara-RVd: SC Daratumumab, Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Sonneveld et al. 2023 (PERSEUS)	2019-01-19 to 2020-01-03	Phase 3 (E-RT-esc)	RVD 	Longer PFS (primary endpoint)PFS48: 84.3% vs 67.7%(HR 0.42, 95% CI 0.30-0.59)
====Targeted therapy====
*Daratumumab and hyaluronidase (Darzalex Faspro) as follows:
**Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22
**Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 9 to 12
28-day cycle for 6 cycles
====Subsequent treatment====
*Melphalan, then auto HSCT consolidation, then Lenalidomide maintenance
===References===
# PERSEUS: Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, Hulin C, Antonioli E, Leleu X, Mangiacavalli S, Perrot A, Cavo M, Belotti A, Broijl A, Gay F, Mina R, Nijhof IS, van de Donk NWCJ, Katodritou E, Schjesvold F, Sureda Balari A, Rosiñol L, Delforge M, Roeloffzen W, Silzle T, Vangsted A, Einsele H, Spencer A, Hajek R, Jurczyszyn A, Lonergan S, Ahmadi T, Liu Y, Wang J, Vieyra D, van Brummelen EMJ, Vanquickelberghe V, Sitthi-Amorn A, de Boer CJ, Carson R, Rodriguez-Otero P, Bladé J, Moreau P; PERSEUS Trial Investigators. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Jan 25;390(4):301-313. Epub 2023 Dec 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03710603
==Dara-VMP==
Dara-VMP: Daratumumab, Velcade (Bortezomib), Melphalan, Prednisone
D-VMP: Daratumumab, Velcade (Bortezomib), Melphalan, Prednisone
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Mateos et al. 2017 (ALCYONE)	2015-02-09 to 2016-07-14	Phase 3 (E-RT-esc)	VMP 	Longer PFS (primary endpoint)PFS18: 71.6% vs 50.2%(HR 0.50, 95% CI 0.38-0.65)Longer OS1 (secondary endpoint)OS36: 78% vs 68% (HR 0.60, 95% CI 0.46-0.80)
1Reported OS efficacy is based on the 2019 update.
Note: This regimen was intended for patients with newly diagnosed multiple myeloma who were not eligible for high-dose chemotherapy with stem-cell transplantation owing to coexisting conditions or an age of 65 years or older. Note that dexamethasone is substituted for prednisone on day 1.
====Targeted therapy====
*Daratumumab (Darzalex) as follows:
**Cycle 1: 16 mg/kg IV once per day on days 1, 8, 15, 22, 29, 36
**Cycles 2 to 9: 16 mg/kg IV once per day on days 1 & 22
*Bortezomib (Velcade) as follows:
**Cycle 1: 1.3 mg/m2 SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
**Cycles 2 to 9: 1.3 mg/m2 SC once per day on days 1, 8, 22, 29
====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 2 to 4
====Supportive therapy====
*Dexamethasone (Decadron) as follows:
**Cycle 1: 20 mg IV or PO once per day on days 1, 8, 15, 22, 29, 36, prior to daratumumab
**Cycles 2 to 9: 20 mg IV or PO once per day on days 1 & 22, prior to daratumumab
42-day cycle for 9 cycles
====Subsequent treatment====
*Daratumumab maintenance
===References===
# ALCYONE: Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Kaplan P, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Chiu C, Wang J, Carson R, Crist W, Deraedt W, Nguyen H, Qi M, San-Miguel J; ALCYONE Trial Investigators. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. Epub 2017 Dec 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02195479
## Update: Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, Knop S, Doyen C, Lucio P, Nagy Z, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Iosava G, Fujisaki T, Garg M, Krevvata M, Chen Y, Wang J, Kudva A, Ukropec J, Wroblewski S, Qi M, Kobos R, San-Miguel J. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020 Jan 11;395(10218):132-141. Epub 2019 Dec 10. link to original article EuroPMC
##HRQoL analysis: Knop S, Mateos MV, Dimopoulos MA, Suzuki K, Jakubowiak A, Doyen C, Lucio P, Nagy Z, Usenko G, Pour L, Cook M, Grosicki S, Crepaldi A, Liberati AM, Campbell P, Shelekhova T, Yoon SS, Losava G, Fujisaki T, Garg M, Wang J, Wroblewski S, Kudva A, Gries KS, Fastenau J, San-Miguel J, Cavo M. Health-related quality of life in patients with newly diagnosed multiple myeloma ineligible for stem cell transplantation: results from the randomized phase III ALCYONE trial. BMC Cancer. 2021 Jun;21(1):659. link to original article link to EuroPMC
==Dara-VMP (SC daratumumab)==
Dara-VMP: Daratumumab and hyaluronidase, Velcade (Bortezomib), Melphalan, Prednisone
D-VMP: Daratumumab and hyaluronidase, Velcade (Bortezomib), Melphalan, Prednisone
===Regimen===
Study 	Dates of enrollment 	Evidence
Chari et al. 2020 (PLEIADES)	2018 to not reported	Phase 2 (RT)
====Targeted therapy====
*Daratumumab and hyaluronidase (Darzalex Faspro) as follows:
**Cycle 1: 1800 mg SC once per day on days 1, 8, 15, 22, 29, 36
**Cycles 2 to 9: 1800 mg SC once per day on days 1 & 22
**Cycle 10 onwards: 1800 mg SC once on day 1
*Bortezomib (Velcade) as follows:
**Cycle 1: 1.3 mg/m2 SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
**Cycles 2 to 9: 1.3 mg/m2 SC once per day on days 1, 8, 22, 29
====Chemotherapy====
*Melphalan (Alkeran) as follows:
**Cycles 1 to 9: 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycles 1 to 9: 60 mg/m2 PO once per day on days 1 to 4
42-day cycle for 9 cycles, then 28-day cycles
===References===
#PLEIADES: Chari A, Rodriguez-Otero P, McCarthy H, Suzuki K, Hungria V, Sureda Balari A, Perrot A, Hulin C, Magen H, Iida S, Maisnar V, Karlin L, Pour L, Parasrampuria DA, Masterson T, Kosh M, Yang S, Delioukina M, Qi M, Carson R, Touzeau C. Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open-label Phase II study. Br J Haematol. 2021 Mar;192(5):869-878. Epub 2020 Jul 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03412565
==Dara-VTD==
Dara-VTD: Daratumumab, Velcade (Bortezomib), Thalidomide, Dexamethasone
D-VTD: Daratumumab, Velcade (Bortezomib), Thalidomide, Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Moreau et al. 2019 (CASSIOPEIA part 1)	2015-2017 	Phase 3 (E-RT-esc)	VTD 	Higher sCR rate (primary endpoint)Longer PFS (secondary endpoint)Median PFS: NYR vs NYR(HR 0.47, 95% CI 0.33-0.67)
Note: This regimen was intended for patients with newly diagnosed multiple myeloma who were eligible for high-dose chemotherapy with stem-cell transplantation.
====Targeted therapy====
*Daratumumab (Darzalex) as follows:
**Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
**Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 100 mg PO once per day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 & 2: 40 mg PO or IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23
**Cycles 3 & 4: 40 mg PO or IV once per day on days 1 & 2, then 20 mg PO or IV once per day on days 8, 9, 15, 16
28-day cycle for 4 cycles
====Subsequent treatment====
*Melphalan with auto HSCT, then Dara-VTD consolidation
===References===
# CASSIOPEIA part 1: Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, Béné MC, Broijl A, Caillon H, Caillot D, Corre J, Delforge M, Dejoie T, Doyen C, Facon T, Sonntag C, Fontan J, Garderet L, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Lenain P, Macro M, Mathiot C, Orsini-Piocelle F, Perrot A, Stoppa AM, van de Donk NW, Wuilleme S, Zweegman S, Kolb B, Touzeau C, Roussel M, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Fermand JP, Escoffre-Barbe M, Eveillard JR, Garidi R, Ahmadi T, Zhuang S, Chiu C, Pei L, de Boer C, Smith E, Deraedt W, Kampfenkel T, Schecter J, Vermeulen J, Avet-Loiseau H, Sonneveld P. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019 Jul 6;394(10192):29-38. Epub 2019 Jun 3. Erratum in: Lancet. 2019 Jun 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02541383
##HRQoL analysis: Roussel M, Moreau P, Hebraud B, Laribi K, Jaccard A, Dib M, Slama B, Dorvaux V, Royer B, Frenzel L, Zweegman S, Klein SK, Broijl A, Jie KS, Wang J, Vanquickelberghe V, de Boer C, Kampfenkel T, Gries KS, Fastenau J, Sonneveld P. Bortezomib, thalidomide, and dexamethasone with or without daratumumab for transplantation-eligible patients with newly diagnosed multiple myeloma (CASSIOPEIA): health-related quality of life outcomes of a randomised, open-label, phase 3 trial. Lancet Haematol. 2020 Dec;7(12):e874-e883. link to original article EuroPMC
##Update: Moreau P, Hulin C, Perrot A, Arnulf B, Belhadj K, Benboubker L, Zweegman S, Caillon H, Caillot D, Avet-Loiseau H, Delforge M, Dejoie T, Facon T, Sonntag C, Fontan J, Mohty M, Jie KS, Karlin L, Kuhnowski F, Lambert J, Leleu X, Macro M, Orsini-Piocelle F, Roussel M, Schiano de Colella JM, van de Donk NW, Wuillème S, Broijl A, Touzeau C, Tiab M, Marolleau JP, Meuleman N, Vekemans MC, Westerman M, Klein SK, Levin MD, Offner F, Escoffre-Barbe M, Eveillard JR, Garidi R, Hua W, Wang J, Tuozzo A, de Boer C, Rowe M, Vanquickelberghe V, Carson R, Vermeulen J, Corre J, Sonneveld P; Intergroupe Francophone du Myélome, the Dutch-Belgian Cooperative Trial Group for Hematology Oncology and the CASSIOPEIA Investigators. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024 Aug;25(8):1003-1014. Epub 2024 Jun 15. link to original article EuroPMC
==Isa-RVd==
Isa-RVd: Isatuximab, Revlimid (Lenalidomide), Velcade (Bortezomib), low-dose dexamethasone
Isa-VRd: Isatuximab, Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone
===Regimen variant #1, transplant-eligible===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Goldschmidt et al. 2022 (GMMG-HD7)	2018-2020 	Phase 3 (E-esc)	RVd 	Higher MRD negativity (primary endpoint)MRD negativity: 50% vs 36%(OR 1.82, 95% CI 1.33-2.48)
Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 18-70, WHO performance status 0-2, and eligible for stem cell transplant.
====Targeted therapy====
*Isatuximab (Sarclisa) as follows:
**Cycle 1: 10 mg/kg IV once per day on days 1, 8, 15, 22, 29
**Cycles 2 & 3: 10 mg/kg IV once per day on days 1, 15, 29
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14, 22 to 35
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33
42-day cycle for 3 cycles
====Subsequent treatment====
*CAD & G-CSF stem cell mobilization, then melphalan, then auto HSCT consolidation
===Regimen variant #2, transplant-ineligible option #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Facon et al. 2024 (IMROZ)	2017-12 to 2019-03 	Phase 3 (E-RT-esc)	RVd 	Longer PFS (primary endpoint)PFS60: 63.2% vs 45.2%(HR 0.60, 98.5% CI 0.41-0.88)
Note: This regimen was intended for patients with newly diagnosed multiple myeloma aged 65 to 80 or otherwise ineligible for stem cell transplant.
====Targeted therapy====
*Isatuximab (Sarclisa) as follows:
**Cycle 1: 10 mg/kg IV once per day on days 1, 8, 15, 22, 29, 36
**Cycles 2 to 4: 10 mg/kg IV once per day on days 1, 15, 29
*Lenalidomide (Revlimid) by the following laboratory-based criteria:
**eGFR 60 mL/min/1.73m2 or more: 25 mg PO once per day on days 1 to 14, 22 to 35
**eGFR 30 up to 60 mL/min/1.73m2: 10 mg PO once per day on days 1 to 14, 22 to 35
*Bortezomib (Velcade) 1.3 mg/m2 SC once per day on days 1, 4, 8, 11, 22, 25, 29, 32
====Glucocorticoid therapy====
*Dexamethasone (Decadron) by the following age-based criteria:
**Younger than 75 years old: 20 mg PO or IV once per day on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 22, 23, 25, 26, 29, 30, 32, 33
**75 years old or older: 20 mg PO or IV once per day on days 1, 4, 8, 11, 15, 22, 25, 29, 32
42-day cycle for 4 cycles
====Subsequent treatment====
*Isa-Rd maintenance
===Regimen variant #3, transplant-ineligible option #2===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Leleu et al. 2024 (BENEFIT)	2021-09-07 to 2022-09-02	Phase 3 (E-esc)	Isa-Rd 	Higher MRD- at 18 mo (primary endpoint)MRD- at 18 mo: 53% vs 26%
====Targeted therapy====
*Isatuximab (Sarclisa) as follows:
**Cycle 1: 10 mg/kg IV once per day on days 1, 8, 15, 22
**Cycles 2 to 12: 10 mg/kg IV once per day on days 1 & 15
**Cycles 13 to 18: 10 mg/kg IV once on day 1
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
*Bortezomib (Velcade) as follows:
**Cycles 1 to 12: 1.3 mg/m2 SC once per day on days 1, 8, 15
**Cycles 13 to 18: 1.3 mg/m2 SC once per day on days 1 & 15
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycles 1 to 12: 20 mg PO once per day on days 1, 8, 15, 22
28-day cycle for 18 cycles
====Subsequent treatment====
*Len-Isa maintenance
===References===
#GMMG-HD7: Goldschmidt H, Mai EK, Bertsch U, Fenk R, Nievergall E, Tichy D, Besemer B, Dürig J, Schroers R, von Metzler I, Hänel M, Mann C, Asemissen AM, Heilmeier B, Weinhold N, Huhn S, Kriegsmann K, Luntz SP, Holderried TAW, Trautmann-Grill K, Gezer D, Klaiber-Hakimi M, Müller M, Khandanpour C, Knauf W, Scheid C, Munder M, Geer T, Riesenberg H, Thomalla J, Hoffmann M, Raab MS, Salwender HJ, Weisel KC; German-Speaking Myeloma Multicenter Group (GMMG) HD7 investigators. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial. Lancet Haematol. 2022 Nov;9(11):e810-e821. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03617731
#IMROZ: Facon T, Dimopoulos MA, Leleu XP, Beksac M, Pour L, Hájek R, Liu Z, Minarik J, Moreau P, Romejko-Jarosinska J, Spicka I, Vorobyev VI, Besemer B, Ishida T, Janowski W, Kalayoglu-Besisik S, Parmar G, Robak P, Zamagni E, Goldschmidt H, Martin TG, Manier S, Mohty M, Oprea C, Brégeault MF, Macé S, Berthou C, Bregman D, Klippel Z, Orlowski RZ; IMROZ Study Group. Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Oct 31;391(17):1597-1609. Epub 2024 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03319667
#BENEFIT: Leleu X, Hulin C, Lambert J, Bobin A, Perrot A, Karlin L, Roussel M, Montes L, Cherel B, Chalopin T, Slama B, Chretien ML, Laribi K, Dingremont C, Roul C, Mariette C, Rigaudeau S, Calmettes C, Dib M, Tiab M, Vincent L, Delaunay J, Santagostino A, Macro M, Bourgeois E, Orsini-Piocelle F, Gay J, Bareau B, Bigot N, Vergez F, Lebreton P, Tabrizi R, Waultier-Rascalou A, Frenzel L, Le Calloch R, Chalayer E, Braun T, Lachenal F, Corm S, Kennel C, Belkhir R, Bladé JS, Joly B, Richez-Olivier V, Gardeney H, Demarquette H, Robu-Cretu D, Garderet L, Newinger-Porte M, Kasmi A, Royer B, Decaux O, Arnulf B, Belhadj K, Touzeau C, Mohty M, Manier S, Moreau P, Avet-Loiseau H, Corre J, Facon T. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial. Nat Med. 2024 Aug;30(8):2235-2241. Epub 2024 Jun 3. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04751877
==KRdc==
KRdc: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), low-dose dexamethasone, low-dose cyclophosphamide
===Regimen ===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jackson et al. 2021 (UK NCRI Myeloma XI+)	2013-2016 	Phase 3 (E-esc)	1. Rdc2. Tdc	Longer PFS (co-primary endpoint)Median PFS: NYR vs 36.1 mo(HR 0.63, 95% CI 0.51-0.76)
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1 & 8
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4, 8, 9, 15, 16
====Targeted therapy====
*Carfilzomib (Kyprolis) as follows:
**Cycle 1: 20 mg/m2 IV once per day on days 1 & 2, then 36 mg/m2 IV once per day on days 8, 9, 15, 16
**Cycle 2 onwards: 36 mg/m2 IV once per day on days 1, 2, 8, 9, 15, 16
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for at least 4 cycles
====Subsequent treatment====
*Melphalan, then auto HSCT consolidation, then Lenalidomide maintenance versus Observation
===References===
# UK NCRI Myeloma XI+: Jackson GH, Pawlyn C, Cairns DA, de Tute RM, Hockaday A, Collett C, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Rocci A, Snowden JA, Jenner MW, Cook G, Russell NH, Drayson MT, Gregory WM, Kaiser MF, Owen RG, Davies FE, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial. PLoS Med. 2021 Jan 11;18(1):e1003454. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01554852
==RVDC==
RVDC: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VDCR: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide, Revlimid (Lenalidomide)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	1. VDC 	No formal comparison
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	2. VDC; modified	No formal comparison
Kumar et al. 2012 (EVOLUTION)	2008-2009 	Randomized Phase 2 (E-esc)	3. VDR 	No formal comparison
Note: This regimen was intended for patients greater than or equal to 18 years of age with previously untreated symptomatic MM, with measurable disease and a Karnofsky Performance Status greater than or equal to 50%, regardless of their eligibility for autologous hematopoietic cell transplantation.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 14
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
====Supportive therapy====
*Aspirin 325 mg PO once per day 
**Warfarin (Coumadin) or Enoxaparin (Lovenox) could be used based on physician discretion
*PCP prophylaxis recommended
*Acyclovir (Zovirax) prophylaxis for Herpes zoster recommended
*Bisphosphonates could be used "as necessary"
21-day cycle for 8 cycles
====Subsequent treatment====
*Bortezomib consolidation
===References===
# EVOLUTION: Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, Stewart AK, Turturro F, Rifkin R, Wolf J, Estevam J, Mulligan G, Shi H, Webb IJ, Rajkumar SV. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood. 2012 May 10;119(19):4375-82. Epub 2012 Mar 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00507442
==VMPT==
VMPT: Velcade (Bortezomib), Melphalan, Prednisone, Thalidomide
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Palumbo et al. 2010 (GIMEMA MM-03-05)	2006-05 to 2009-01 	Phase 3 (E-esc)	VMP 	Longer PFS (primary endpoint)PFS36: 56% vs 41%(HR 0.67, 95% CI 0.50-0.90)Longer OS1 (secondary endpoint)OS60: 61% vs 51%(HR 0.70, 95% CI 0.52-0.92)
1Reported OS efficacy is based on the 2014 update.
Note: This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities.
====Targeted therapy====
*Bortezomib (Velcade) as follows:
**Cycles 1 to 4: 1.3 mg/m2 IV bolus once per day on days 1, 4, 8, 11, 22, 25, 29, 32
**Cycles 5 to 9: 1.3 mg/m2 IV bolus once per day on days 1, 8, 22, 29
*Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 42
====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
====Subsequent treatment====
*VT maintenance
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Palumbo et al. 2010 (GIMEMA MM-03-05)	2006-05 to 2009-01 	Phase 3 (E-esc)	VMP 	Longer PFS (primary endpoint)PFS36: 56% vs 41%(HR 0.67, 95% CI 0.50-0.90)Longer OS1 (secondary endpoint)OS60: 61% vs 51%(HR 0.70, 95% CI 0.52-0.92)
1Reported efficacy is based on the 2014 update.
Note: This regimen was intended for patients with newly diagnosed myeloma who were not candidates for high-dose therapy plus stem-cell transplantation because of age (greater than or equal to 65 years) or coexisting comorbidities. This variant represents a mid-protocol change (in 2007) where cycle length was decreased from 6 to 5 weeks and bortezomib was changed to weekly dosing.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV bolus once per day on days 1, 8, 15, 22
*Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 42
====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
====Subsequent treatment====
*VT maintenance
===References===
# GIMEMA MM-03-05: Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T, Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Falcone AP, Gottardi D, Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010 Dec 1;28(34):5101-9. Epub 2010 Oct 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01063179
## Post-hoc analysis: Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010 Dec 2;116(23):4745-53. Epub 2010 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Subgroup analysis: Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, Benevolo G, Magarotto V, Tacchetti P, Pescosta N, Cellini C, Polloni C, Evangelista A, Caravita T, Morabito F, Offidani M, Tosi P, Boccadoro M. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011 Mar 10;29(8):986-93. Epub 2011 Jan 31. link to original article EuroPMC
## Subgroup analysis: Morabito F, Gentile M, Mazzone C, Rossi D, Di Raimondo F, Bringhen S, Ria R, Offidani M, Patriarca F, Nozzoli C, Petrucci MT, Benevolo G, Vincelli I, Guglielmelli T, Grasso M, Marasca R, Baldini L, Montefusco V, Musto P, Cascavilla N, Majolino I, Musolino C, Cavo M, Boccadoro M, Palumbo A. Safety and efficacy of bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT) versus bortezomib-melphalan-prednisone (VMP) in untreated multiple myeloma patients with renal impairment. Blood. 2011 Nov 24;118(22):5759-66. Epub 2011 Sep 27. link to original article EuroPMC
## Update: Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V, Patriarca F, Levi A, Benevolo G, Vincelli ID, Grasso M, Franceschini L, Gottardi D, Zambello R, Montefusco V, Falcone AP, Omedé P, Marasca R, Morabito F, Mina R, Guglielmelli T, Nozzoli C, Passera R, Gaidano G, Offidani M, Ria R, Petrucci MT, Musto P, Boccadoro M, Cavo M. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014 Mar 1;32(7):634-40. Epub 2014 Jan 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=First-line therapy, other=
==CVAD==
CVAD: Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX)	2003-2007 	Phase 3 (C)	CTD 	Not reported
Note: This was an intensive treatment pathway, as determined by performance status, informed discussion, and patient preference. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg PO once per day on days 1, 8, 15
*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, 12 to 15
====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
21-day cycle for 4 to 6 cycles until maximum response
====Subsequent treatment====
*MRC Myeloma IX, responding patients: High-dose melphalan and autologous hematopoietic cell transplant consolidation
===References===
# MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article EuroPMC ISRCTN68454111
## Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article EuroPMC
==TVAD (Pegylated liposomal doxorubicin substituted)==
TVAD doxil: Thalidomide, Vincristine, pegylated liposomal Adriamycin (Doxil), Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Zervas et al. 2007	2002-2006 	Phase 3 (E-esc)	VAD doxil 	Seems to have longer OS (secondary endpoint)OS24: 77% vs 64.6%(HR not reported, p=0.037)Higher ORR (primary endpoint)
Note: This trial was open to patients aged 18 to 75 years old with previously untreated symptomatic MM and a life expectancy of greater than 6 months.
====Targeted therapy====
*Thalidomide (Thalomid) 200 mg PO once per day
====Chemotherapy====
*Vincristine (Oncovin) 2 mg IV once on day 1
*Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV over 60 minutes once on day 1
====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
28-day cycle for 4 cycles
===References===
# Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol. 2007 Aug;18(8):1369-75. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==VAD (Pegylated liposomal doxorubicin substituted)==
DVD: Doxil (Pegylated liposomal doxorubicin), Vincristine, Dexamethasone
DVd: Doxil (Pegylated liposomal doxorubicin), Vincristine, low-dose dexamethasone
VAD doxil: Vincristine, Pegylated liposomal Adriamycin (Doxil), Dexamethasone
===Regimen variant #1, indefinite ("DVd")===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rifkin et al. 2006 (CR002434)	2001-2003 	Phase 3 (E-switch-ic)	VAd 	Non-inferior ORR (co-primary endpoint)
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.
====Chemotherapy====
*Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV over 60 minutes once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV over 5 minutes once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
28-day cycles
===Regimen variant #2, limited duration (4 cycles)===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Dimopoulos et al. 2003	1999-2001 	Phase 3 (E-switch-ic)	VAD 	Did not meet primary endpoint of ORR
Zervas et al. 2007 	2002-2006 	Phase 3 (C) 	TVAD-Doxil	Seems to have shorter OS (secondary endpoint)OS24: 64.4% vs 77%(HR not reported, p=0.037)Lower ORR (primary endpoint)
Note: Dimopoulos et al. 2003 was open to all patients with previously untreated multiple myeloma who were considered candidates for systemic treatment. Zervas et al. 2007 was open to patients aged 18 to 75 years old with previously untreated symptomatic MM and a life expectancy of greater than 6 months.
====Chemotherapy====
*Vincristine (Oncovin) 2 mg IV once on day 1
*Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV over 60 minutes once on day 1
====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====
*In the cited Segeren et al. 1999 VAD protocol reference:
*Fluconazole (Diflucan) 200 mg PO once per day 
*Trimethoprim/Sulfamethoxazole 960 mg (paper did not specify which component was 960 mg) PO twice per day for "prophylaxis"
28-day cycle for 4 cycles
===Regimen variant #3, limited duration (6 to 8 cycles)===
Study 	Dates of enrollment	Evidence
Hussein et al. 2002	Not reported 	Phase 2
====Chemotherapy====
*Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4
====Supportive therapy====
*Vitamin B6 200 mg PO once per day to help reduce risk of palmar-plantar erythrodysesthesia (PPE)
28-day cycle for 6 to 8 cycles
===References===
# Hussein MA, Wood L, Hsi E, Srkalovic G, Karam M, Elson P, Bukowski RM. A Phase II trial of pegylated liposomal doxorubicin, vincristine, and reduced-dose dexamethasone combination therapy in newly diagnosed multiple myeloma patients. Cancer. 2002 Nov 15;95(10):2160-8. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Dimopoulos MA, Pouli A, Zervas K, Grigoraki V, Symeonidis A, Repoussis P, Mitsouli C, Papanastasiou C, Margaritis D, Tokmaktsis A, Katodritou I, Kokkini G, Terpos E, Vyniou N, Tzilianos M, Chatzivassili A, Kyrtsonis MC, Panayiotidis P, Maniatis A; Greek Myeloma Study Group. Prospective randomized comparison of vincristine, doxorubicin and dexamethasone (VAD) administered as intravenous bolus injection and VAD with liposomal doxorubicin as first-line treatment in multiple myeloma. Ann Oncol. 2003 Jul;14(7):1039-44. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# CR002434: Rifkin RM, Gregory SA, Mohrbacher A, Hussein MA. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a phase III multicenter randomized trial. Cancer. 2006 Feb 15;106(4):848-58. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00344422
# Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli CH, Anagnostopoulos A, Delibasi S, Kyrtsonis MC, Anagnostopoulos N, Terpos E, Zikos P, Maniatis A, Dimopoulos MA; Greek Myeloma Study Group. VAD-doxil versus VAD-doxil plus thalidomide as initial treatment for multiple myeloma: results of a multicenter randomized trial of the Greek Myeloma Study Group. Ann Oncol. 2007 Aug;18(8):1369-75. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==VAD-P==
VAD-P: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Berenson et al. 2002 (SWOG 9210)	1993-1997 	Phase 3 (C)	VAD-P/Q 	Did not meet primary endpoint
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====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)
**Poor-risk patients received 6.75 mg/m2/day in cycle 1 (total dose 27 mg/m2), with increase to full dose starting cycle 2 if no undue toxicity
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
*Prednisone (Sterapred) 50 mg PO once per day on days 9, 11, 13, 15, 17, 19
21-day cycle for at least 9 cycles (6 months) or until at least 25% regression of disease
====Subsequent treatment====
*SWOG 9210, patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy: prednisone; low-dose versus prednisone; high-dose maintenance
===References===
# SWOG 9210: Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==VAD-P/Q==
VAD-P/Q: Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Prednisone, Quinine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Berenson et al. 2002 (SWOG 9210)	1993-1997 	Phase 3 (E-esc)	VAD-P 	Did not meet primary endpoint
====Chemotherapy====
*Vincristine (Oncovin) 0.4 mg/day IV continuous infusion over 96 hours, started on day 2 (total dose per cycle: 1.6 mg)
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 2 (total dose per cycle: 36 mg/m2) 
**Poor-risk patients received 6.75 mg/m2/day in cycle 1 (total dose 27 mg/m2), with increase to full dose starting cycle 2 if no undue toxicity
*Quinine (Qualaquin) 400 mg PO three times per day on days 1 to 6
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 2 to 5
*Prednisone (Sterapred) 50 mg PO once per day on days 10, 12, 14, 16, 18, 20
21-day cycle for at least 6 months or until at least 25% regression of disease
====Subsequent treatment====
*SWOG 9210, patients with at least 50% regression in 6 months or 25% regression in 9 to 12 months of therapy: prednisone; low-dose versus prednisone; high-dose maintenance
===References===
# SWOG 9210: Berenson JR, Crowley JJ, Grogan TM, Zangmeister J, Briggs AD, Mills GM, Barlogie B, Salmon SE. Maintenance therapy with alternate-day prednisone improves survival in multiple myeloma patients. Blood. 2002 May 1;99(9):3163-8. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==VMP, then Rd==
VMP, then Rd: Velcade (Bortezomib), Melphalan, Prednisone, followed by Revlimid (Lenalidomide), low dose dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Mateos et al. 2015 (PETHEMA GEM05)	2005 to not reported	Phase 3 (E-switch-ic)	VMP/Rd 	Did not meet primary endpoint of PFS18PFS18: 74% vs 80%
Note: This regimen was intended for patients aged greater than or equal to 65 years with newly diagnosed, untreated, symptomatic, measurable MM.
====Targeted therapy, VMP portion====
*Bortezomib (Velcade) as follows:
**Cycle 1: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
**Cycles 2 to 9: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
====Chemotherapy, VMP portion (cycles 1 to 9)====
*Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy, VMP portion (cycles 1 to 9)====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
====Supportive therapy, VMP portion (cycles 1 to 9)====
*Bisphosphonates 
*Prophylactic antiviral therapy
====Targeted therapy, Rd portion (cycles 10 to 18)====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy, Rd portion (cycles 10 to 18)====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
====Supportive therapy, Rd portion (cycles 10 to 18)====
*Mandatory thromboprophylaxis with one of the following choices:
**Aspirin
**low–molecular weight heparin
42-day course, 28-day cycle for 17 cycles (VMP x 9; Rd x 9)
===References===
# PETHEMA GEM05: Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00443235
==VMP/Rd==
VMP/Rd: Velcade (Bortezomib), Melphalan, Prednisone alternating with Revlimid (Lenalidomide), low dose dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Mateos et al. 2015 (PETHEMA GEM05)	2005 to not reported	Phase 3 (E-switch-ic)	VMP, then Rd	Did not meet primary endpoint of PFS18
Note: This regimen was intended for patients aged greater than or equal to 65 years with newly diagnosed, untreated, symptomatic, measurable MM.
====Targeted therapy, VMP portion====
*Bortezomib (Velcade) as follows:
**Cycle 1: 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, 22, 25, 29, 32
**Cycles 3, 5, 7, 9, 11, 13, 15, 17: 1.3 mg/m2 IV once per day on days 1, 8, 15, 22
====Chemotherapy, VMP portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)====
*Melphalan (Alkeran) 9 mg/m2 PO once per day on days 1 to 4
====Glucocorticoid therapy, VMP portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 4
====Supportive therapy, VMP portion (cycles 1, 3, 5, 7, 9, 11, 13, 15, 17)====
*Bisphosphonates 
*Prophylactic antiviral therapy
====Targeted therapy, Rd portion (cycles 2, 4, 6, 8, 10, 12, 14, 16, 18)====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
====Glucocorticoid therapy, Rd portion (cycles 2, 4, 6, 8, 10, 12, 14, 16, 18)====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1, 8, 15, 22
====Supportive therapy, Rd portion (cycles 2, 4, 6, 8, 10, 12, 14, 16, 18)====
*Mandatory thromboprophylaxis with one of the following choices: 
**Aspirin
**Low–molecular weight heparin
42-day course, then 28-day cycle for 17 cycles
===References===
# PETHEMA GEM05: Mateos MV, Martínez-López J, Hernández MT, Ocio EM, Rosiñol L, Martínez R, Teruel AI, Gutiérrez NC, Martín Ramos ML, Oriol A, Bargay J, Bengoechea E, González Y, Pérez de Oteyza J, Gironella M, Encinas C, Martín J, Cabrera C, Paiva B, Cedena MT, Puig N, Bladé J, Lahuerta JJ, San-Miguel J. Sequential vs alternating administration of VMP and Rd in elderly patients with newly diagnosed MM. Blood. 2016 Jan 28;127(4):420-5. Epub 2015 Oct 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00443235
==Zoledronic acid therapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Morgan et al. 2010 (MRC Myeloma IX)	2003-2007 	Phase 3 (E-switch-ic)	Clodronic acid	Seems to have longer OS (co-primary endpoint)Median OS: 50 vs 44.5 mo(HR 0.84, 95% CI 0.74-0.96)
Note: this agent was not given as monotherapy, but is included separately from the regimens that it was given with, based on the RCT design.
====Supportive therapy====
*Zoledronic acid (Zometa) as follows:
**During induction: 4 mg IV over 15 minutes once every 3 to 4 weeks
**Consolidation onwards: 4 mg IV over 15 minutes once every 4 weeks
Continued indefinitely
===References===
# MRC Myeloma IX: Morgan GJ, Davies FE, Gregory WM, Cocks K, Bell SE, Szubert AJ, Navarro-Coy N, Drayson MT, Owen RG, Feyler S, Ashcroft AJ, Ross F, Byrne J, Roddie H, Rudin C, Cook G, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Study Group. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet. 2010 Dec 11;376(9757):1989-99. Epub 2010 Dec 3. link to original article link to PMC article EuroPMC ISRCTN68454111
## Update: Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; NCRI Haematological Oncology Study Group. Cyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple myeloma unsuitable for autologous transplantation. Blood. 2011 Aug 4;118(5):1231-8. Epub 2011 Jun 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Morgan GJ, Gregory WM, Davies FE, Bell SE, Szubert AJ, Brown JM, Coy NN, Cook G, Russell NH, Rudin C, Roddie H, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012 Jan 5;119(1):7-15. Epub 2011 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Johnson PR, Rudin C, Drayson MT, Owen RG, Ross FM, Russell NH, Jackson GH, Child JA; National Cancer Research Institute Haematological Oncology Clinical Studies Group. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica. 2012 Mar;97(3):442-50. Epub 2011 Nov 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
## Update: Morgan GJ, Davies FE, Gregory WM, Bell SE, Szubert AJ, Cook G, Drayson MT, Owen RG, Ross FM, Jackson G, Child JA. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013 Nov 1;19(21):6030-8. Epub 2013 Aug 30. link to original article EuroPMC
==Total Therapy==
Study 	Dates of enrollment	Evidence
Barlogie et al. 1997 (Total Therapy 1)	1990-1994 	Non-randomized
Barlogie et al. 2006 (Total Therapy 2)	1998-2004 	Prospective with randomization
Barlogie et al. 2007 (Total Therapy 3)	2004-2006 	Prospective
Note: Total Therapy is a very complicated protocol, you are highly recommended to refer to the original manuscripts for further details. Total Therapy 3 is replicated here; the references for Total Therapy 2 are provided below but there are no plans to add this regimen here, for now.
===Induction, VTD-PACE===
VTD-PACE: Velcade (Bortezomib), Thalidomide, Dexamethasone, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide
====Targeted therapy====
*Bortezomib (Velcade) 1 mg/m2 SC once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 200 mg PO once per day on days 4 to 7
====Glucocorticoid therapy=====
*Dexamethasone (Decadron) 40 mg PO once per day on days 4 to 7
====Chemotherapy=====
*Cisplatin (Platinol) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m2)
*Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m2)
*Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 1600 mg/m2)
*Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 160 mg/m2)
*Peripheral blood stem cells (PBSC) are usually collected during cycle 1--cycle 2 PBSC collection is done if needed--with a median CD34 count of 29 x 106/kg. 87% of collections yielded at least 20 x 106/kg.
====Supportive therapy====
*As described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.
*Filgrastim (Neupogen) "was administered to support induction and consolidation chemotherapy regimens"
*"Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
*Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide
Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart
During the interim period between cycle 1 and cycle 2, as well as after cycle 2 and prior to transplant, this is given once platelets have recovered to at least 50 x 109/L:
===Interim maintenance, between cycles 1 and 2 of induction===
====Targeted therapy====
*Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
21-day cycles; given between induction cycles and transplant
In other words, the initial therapy consists of: Induction therapy cycle 1, dexamethasone & thalidomide, induction therapy cycle 2, dexamethasone & thalidomide, then transplant.
===Consolidation, auto HSCT===
====Chemotherapy====
Full details were not provided in Barlogie et al. 2007. Tandem autologous transplants were done between 2 to 6 months apart.
*Melphalan (Alkeran) 200 mg/m2 IV (day not specified)
===Interim maintenance, between transplant 1 and transplant 2===
During the interim period after transplant 1 and transplant 2, patients receive:
====Targeted therapy====
*Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
21-day cycles; given in the time between and after each transplant; if platelets less than 50 x 109/L, proceed to year 1 of maintenance therapy. Otherwise, if platelets are at least 50 x 109/L, proceed to consolidation therapy.
Cycle 1 of consolidation starts 1.5 to 4 months after the last transplant. Cycle 2 of consolidation starts 2 to 4 months after cycle 1 of consolidation.
===Consolidation, VTD-PACE===
====Targeted therapy====
*Bortezomib (Velcade) 1 mg/m2 SC once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 200 mg PO once per day on days 1 to 4
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Chemotherapy====
*Cisplatin (Platinol) 7.5 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 30 mg/m2)
*Doxorubicin (Adriamycin) 7.5 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 30 mg/m2)
*Cyclophosphamide (Cytoxan) 300 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1200 mg/m2)
*Etoposide (Vepesid) 30 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 120 mg/m2)
2 cycles total are given according to the interval specified above, with the interim therapy below used
===Interim maintenance, between consolidation cycles 1 & 2===
During the interim period between cycle 1 and cycle 2, as well as after cycle 2 and prior to maintenance therapy, this is given once platelets have recovered to at least 50 x 109/L:
====Targeted therapy====
*Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
21-day cycles; given between consolidation cycles and maintenance
In other words, consolidation therapy consists of: Consolidation therapy cycle 1, dexamethasone & thalidomide, consolidation therapy cycle 2, dexamethasone & thalidomide, then maintenance therapy.
====Supportive therapy====
*As described in Barlogie et al. 2006, which Barlogie et al. 2007 refers to. Note: Barlogie et al. 2007 lists an incorrect title for the reference. See below for the the correct full reference.
*Filgrastim (Neupogen) "was administered to support induction and consolidation chemotherapy regimens"
*"Prophylactic antibiotics, histamine H2 blockers, and recombinant erythropoietin" were given as needed
*Low molecular weight heparin (LMWH) prophylaxis was used for all patients receiving thalidomide
===Maintenance, year 1 (VTD)===
Year 1 of maintenance therapy starts 1 to 4 months after consolidation cycle 2.
====Targeted therapy====
VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone
*Bortezomib (Velcade) 1 mg/m2 SC once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 28
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 8 to 11
28-day cycle for 13 cycles (1 year), then proceed to maintenance therapy years 2 to 3
===Maintenance, years 2 & 3===
TD: Thalidomide, Dexamethasone
====Targeted therapy====
*Thalidomide (Thalomid) 100 mg PO once every other day
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4
28-day cycle for 26 cycles (2 years)
===References===
# Total Therapy 1: Barlogie B, Jagannath S, Vesole DH, Naucke S, Cheson B, Mattox S, Bracy D, Salmon S, Jacobson J, Crowley J, Tricot G. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood. 1997 Feb 1;89(3):789-93. link to original article EuroPMC
## Update: Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D, Tricot G, Munshi N, Fassas A, Singhal S, Mehta J, Anaissie E, Dhodapkar D, Naucke S, Cromer J, Sawyer J, Epstein J, Spoon D, Ayers D, Cheson B, Crowley J. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999 Jan 1;93(1):55-65. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# Total Therapy 2: Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van Rhee F, Fassas A, Zangari M, Hollmig K, Pineda-Roman M, Lee C, Talamo G, Thertulien R, Kiwan E, Krishna S, Fox M, Crowley J. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006 Mar 9;354(10):1021-30. link to original article supportive medication details EuroPMC NCT00083551
## Update: Zangari M, van Rhee F, Anaissie E, Pineda-Roman M, Haessler J, Crowley J, Barlogie B. Eight-year median survival in multiple myeloma after total therapy 2: roles of thalidomide and consolidation chemotherapy in the context of Total Therapy 1. Br J Haematol. 2008 May;141(4):433-44. Epub 2008 Mar 26. link to original article link to PMC article EuroPMC
## Subgroup analysis: Barlogie B, Pineda-Roman M, van Rhee F, Haessler J, Anaissie E, Hollmig K, Alsayed Y, Waheed S, Petty N, Epstein J, Shaughnessy JD Jr, Tricot G, Zangari M, Zeldis J, Barer S, Crowley J. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008 Oct 15;112(8):3115-21. Epub 2008 May 20. link to original article link to PMC article EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
# Total Therapy 3: Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of Total Therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Pineda-Roman M, Zangari M, Haessler J, Anaissie E, Tricot G, van Rhee F, Crowley J, Shaughnessy JD Jr, Barlogie B. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol. 2008 Mar;140(6):625-34. link to original article link to PMC article EuroPMC
## Pooled update: Barlogie B, Attal M, Crowley J, van Rhee F, Szymonifka J, Moreau P, Durie BG, Harousseau JL. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010 Mar 1;28(7):1209-14. Epub 2010 Jan 19. Erratum in: J Clin Oncol. 2010 Jul 20;28(21):3543. link to original article link to PMC article EuroPMC
==VTD-PACE==
VTD-PACE: Velcade (Bortezomib), Thalidomide, Dexamethasone, Platinum (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide
===Synopsis===
The evolution of Total Therapy trials for multiple myeloma at UAMS from Total Therapy 1 (TT1) through Total Therapy 3 (TT3) were historically important innovations in treatment of multiple myeloma, with each trial incorporating advancements in understanding and available therapies for this disease.
 
Total Therapy 1 (TT1) set the foundation set the foundation for these regimens for newly diagnosed multiple myeloma. The focus was on developing a treatment resulting in deep and durable remissions( Barlogie et al., 1999). 
 
The regimen for TT1 included several components:
Remission Induction: This phase used VAD (vincristine, doxorubicin, and dexamethasone) administered three times.
High-Dose Cyclophosphamide with PBSC Collection: Cyclophosphamide was used in high doses (at doses of 1.5 g/m2 every 4 hours x4 for a total of 6 g/m2 along with mesna 6 g/m2 followed by subcutaneous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) 250 μg/m2 beginning on day 2) along with the collection of peripheral blood stem cells (PBSC).
EDAP (aka DECA) Regimen: This included etoposide, dexamethasone, cytarabine, and cisplatin.
Autotransplants: Two autologous stem cell transplants were performed. The preparative regimens for these transplants involved melphalan at a dose of 200 mg/m², or a combination of melphalan at 140 mg/m² and total body irradiation (TBI) ranging from 850 to 1120 cGy, depending on the patient's response to the first transplant.
 
This aggressive and comprehensive approach was designed to induce remission and then reinforce it with high-dose therapy and stem cell transplantation. The success of TT1, as evidenced by higher event-free and overall survival rates compared to standard treatments, established the foundation for the subsequent Total Therapy regimens (TT2 and TT3), which incorporated new drugs and strategies based on emerging research and clinical experience.
 
Total Therapy 2 (TT2) built on the foundation of TT1, with significant changes including the optional addition of thalidomide. Thalidomide was introduced as a new class of medication at the time – immunomodulatory agent therapy, changing the therapeutic landscape of multiple myeloma ( Barlogie et al., 2006).
 
Total Therapy 3 (TT3) further evolved the treatment approach by adding bortezomib and altering the induction and consolidation phases. TT3 applied two cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone; 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide) as induction before and, at reduced doses, as consolidation after melphalan-based tandem transplantation. Maintenance therapy in TT3 comprised VTD (bortezomib [V], thalidomide [T], and dexamethasone [D]) in the first year and TD without V in years 2 and 3​​ ( van Rhee et al., 2010).
 
The evolution from TT1 to TT3 demonstrates an increasingly sophisticated approach to multiple myeloma treatment, integrating new drugs and regimens as medical knowledge and technologies advanced. Each successive trial showed improvements in overall survival, progression-free survival, and complete-response duration
The draft for this synopsis was generated by a large language model and then manually edited by the page editor for accuracy and style. See this page for more information about this pilot project.
===Regimen===
Study 	Dates of enrollment	Evidence
Barlogie et al. 2007 (Total Therapy 3)	2004-2006 	Prospective
Note: this is the induction therapy used in Total Therapy 3. We are not aware of other sources prospectively describing VTD-PACE.
====Targeted therapy====
*Bortezomib (Velcade) 1 mg/m2 SC once per day on days 1, 4, 8, 11
*Thalidomide (Thalomid) 200 mg PO once per day on days 4 to 7
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 4 to 7
====Chemotherapy====
*Cisplatin (Platinol) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m2)
*Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 40 mg/m2)
*Cyclophosphamide (Cytoxan) 400 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 1600 mg/m2)
*Etoposide (Vepesid) 40 mg/m2/day IV continuous infusion over 96 hours, started on day 4 (total dose per cycle: 160 mg/m2)
Duration of each cycle not specified; 2 cycles total are given, no more than 8 weeks apart
===References===
# Total Therapy 3: Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G, Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD Jr. Incorporating bortezomib into upfront treatment for multiple myeloma: early results of Total Therapy 3. Br J Haematol. 2007 Jul;138(2):176-85. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=First-line therapy, intensification=
==VDC==
VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
CVD: Cyclophosphamide, Velcade (Bortezomib), Dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Jackson et al. 2018 (UK NCRI Myeloma XI)	2011-01-13 to 2017-08-11	Phase 3 (E-esc)	No intensification	Longer PFS1 (co-primary endpoint)Median PFS: 30 vs 20 mo(HR 0.60, 95% CI 0.48-0.75)
1Reported efficacy is based on the 2019 manuscript specifically addressing the issue of intensification.
====Preceding treatment====
*CTD versus CRD induction, with minimal or partial response
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV or SC once per day on days 1, 4, 8, 11
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 PO once per day on days 1, 8, 15
21-day cycle for up to 8 cycles
====Subsequent treatment====
*See paper for details
===References===
# UK NCRI Myeloma XI: Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Hockaday A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Jenner MW, Cook G, Russell NH, Kaiser MF, Drayson MT, Owen RG, Gregory WM, Morgan GJ; UK NCRI Haemato-oncology Clinical Studies Group. Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2019 Jan;20(1):57-73. Epub 2018 Dec 14. link to original article link to PMC article EuroPMC NCT01554852
## Update: Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C, Waterhouse A, Jones JR, Kishore B, Garg M, Williams CD, Karunanithi K, Lindsay J, Wilson JN, Jenner MW, Cook G, Kaiser MF, Drayson MT, Owen RG, Russell NH, Gregory WM, Morgan GJ; UK NCRI Haematological Oncology Clinical Studies Group. Response-adapted intensification with cyclophosphamide, bortezomib, and dexamethasone versus no intensification in patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2019 Dec;6(12):e616-e629. Epub 2019 Oct 14. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC
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Category:Multiple myeloma regimens
Category:Disease-specific pages
Category:Plasma cell dyscrasias