Multiple myeloma, relapsed-refractory

Page editor		Section editor
	Mary L. Kwok, MD, FACP Fred Hutchinson Cancer Center Seattle, WA, USA		Samuel M. Rubinstein, MD University of North Carolina Chapel Hill, NC, USA LinkedIn

Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!.
Note: due to its size/complexity, multiple myeloma has been split into sub-pages:

• Induction (transplant eligible and ineligible)
• First-line consolidation and maintenance
• Relapsed/refractory, including subsequent consolidation and maintenance [this page]
• Smoldering multiple myeloma

Last updated on 2024-12-02: 82 regimens on this page 129 variants on this page

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
Please go to the general multiple myeloma page for a list of clinical practice guidelines.

IMWG

• 2024: Lin Y et al. Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple myeloma: a report from the International Myeloma Working Group Immunotherapy Committee PubMed
• 2021: Moreau et al. Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group PubMed

Relapsed or refractory, single agents

Ciltacabtagene autoleucel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Berdeja et al. 2021 (CARTITUDE-1)	2018-07-16 to 2019-10-07	Phase 1b/2 (RT)
San-Miguel et al. 2023 (CARTITUDE-4)	2020-07-10 to 2021-11-17	Phase 3 (E-switch-ooc)	1a. DPd 1b. PVd	Superior PFS (primary endpoint) Median PFS: NYR vs 11.8 mo (HR 0.26, 95% CI 0.18-0.38)

Immunotherapy

• Ciltacabtagene autoleucel (Carvykti) 0.75 x 10⁶ CAR-positive viable T cells/kg IV once on day 0

One course

References

1. CARTITUDE-1: Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, Stewart AK, Hari P, Htut M, Lesokhin A, Deol A, Munshi NC, O'Donnell E, Avigan D, Singh I, Zudaire E, Yeh TM, Allred AJ, Olyslager Y, Banerjee A, Jackson CC, Goldberg JD, Schecter JM, Deraedt W, Zhuang SH, Infante J, Geng D, Wu X, Carrasco-Alfonso MJ, Akram M, Hossain F, Rizvi S, Fan F, Lin Y, Martin T, Jagannath S. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021 Jul 24;398(10297):314-324. Epub 2021 Jun 24. Erratum in: Lancet. 2021 Oct 2;398(10307):1216. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03548207
   1. Update: Martin T, Usmani SZ, Berdeja JG, Agha M, Cohen AD, Hari P, Avigan D, Deol A, Htut M, Lesokhin A, Munshi NC, O'Donnell E, Stewart AK, Schecter JM, Goldberg JD, Jackson CC, Yeh TM, Banerjee A, Allred A, Zudaire E, Deraedt W, Olyslager Y, Zhou C, Pacaud L, Madduri D, Jakubowiak A, Lin Y, Jagannath S. Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up. J Clin Oncol. 2023 Feb 20;41(6):1265-1274. Epub 2022 Jun 4. link to original article link to PMC article PubMed
2. CARTITUDE-4: San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, Fernández de Larrea C, Martínez-López J, Moreau P, Touzeau C, Leleu X, Avivi I, Cavo M, Ishida T, Kim SJ, Roeloffzen W, van de Donk NWCJ, Dytfeld D, Sidana S, Costa LJ, Oriol A, Popat R, Khan AM, Cohen YC, Ho PJ, Griffin J, Lendvai N, Lonardi C, Slaughter A, Schecter JM, Jackson CC, Connors K, Li K, Zudaire E, Chen D, Gilbert J, Yeh TM, Nagle S, Florendo E, Pacaud L, Patel N, Harrison SJ, Einsele H. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med. 2023 Jul 27;389(4):335-347. Epub 2023 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT04181827

Carfilzomib monotherapy

Regimen variant #1, 15/20/27 dosing, for renal impairment

Study	Dates of enrollment	Evidence	Efficacy
Badros et al. 2013 (PX-171-005)	2008-2010	Phase 2	ORR: 25.5%

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 15 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 2: 20 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 3 onwards: 27 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16

Supportive therapy

• Dexamethasone (Decadron) 4 mg (route not specified) before all doses in cycle 1. Continue dexamethasone premedication if patients experience "treatment-related fever, chills, and/or dyspnea."
• "All patients were "required to be well hydrated."

28-day cycle for 12 cycles or longer if deriving clinical benefit

Subsequent treatment

• PX-171-005, patients with less than PR after 2 cycles or less than CR after 4 cycles were allowed to escalate to: Kd

Regimen variant #2, 20/20 dosing

Study	Dates of enrollment	Evidence	Efficacy
Vij et al. 2012b (PX-171-004 bortezomib-exposed)	2007-2008	Phase 2	ORR: 17%
Jagannath et al. 2012 (PX-171-003-A0)	2007-08 to 2008-12	Phase 2	ORR: 17%

Note: Patients enrolled in PX-171-004 could continue therapy beyond 12 cycles on PX-171-010; results of this extension study have not been published, to our knowledge.

Targeted therapy

• Carfilzomib (Kyprolis) 20 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16

28-day cycle for up to 12 cycles (see note)

Regimen variant #3, 20/27 dosing, variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hájek et al. 2016 (FOCUS)	2010-2012	Phase 3 (E-switch-ooc)	1a. Cyclophosphamide & Dexamethasone 1b. CP	Did not meet primary endpoint of OS (HR 0.98, 95% CI 0.76-1.25)

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have ORRs greater than 20%.

Prior treatment criteria

• At least 3 lines of therapy including bortezomib, lenalidomide or thalidomide, an alkylating agent, and corticosteroids

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 10 minutes once per day on days 1 & 2, then 27 mg/m² IV over 10 minutes once per day on days 8, 9, 15, 16
  • Cycles 2 to 9: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 10 onwards: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 15, 16

Supportive therapy

• IV and PO hydration required for cycle 1
• Dexamethasone (Decadron) as follows:
  • Cycle 1: 4 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, given prior to carfilzomib
• Ciprofloxacin (Cipro) as follows:
  • Cycle 1: 500 mg PO once per day

28-day cycles

Regimen variant #4, 20/27 dosing, variant #2

Study	Dates of enrollment	Evidence	Efficacy
Watanabe et al. 2016	2011-2014	Phase 1/2	ORR: 22.5%

Note: This is the maximum predetermined dose, there was no MTD; ORR is reported for the phase 2 portion.

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
  • Cycle 2 onwards: 27 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16

Supportive therapy

• IV and PO hydration required for cycle 1, then as needed
• Dexamethasone (Decadron) as follows:
  • Cycle 1 (required): 4 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, prior to carfilzomib
  • Cycle 2 onwards (prn): 4 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, prior to carfilzomib
• Prophylactic antibiotics (not specified) in cycle 1
• Acyclovir (Zovirax) for patients with history of herpes infection, in cycle 1

28-day cycles

Regimen variant #5, 20/27 dosing, with BSA cap

Study	Dates of enrollment	Evidence	Efficacy
Vij et al. 2012a (PX-171-004 bortezomib-naive)	2007-2010	Phase 2 (RT)	ORR: 42-52%
Siegel et al. 2012 (PX-171-003-A1)	2008-2009	Phase 2 (RT)	ORR: 24%

Note: Neither Vij et al. 2012a nor Siegel et al. 2012 specified that carfilzomib was capped at a body surface area of 2.2 m², but the package insert specifies that: "The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m² should receive a dose based upon a body surface area of 2.2 m². Dose adjustments do not need to be made for weight changes of less than or equal to 20%."

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² (maximum dose of 44 mg; see note) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycles 2 to 12: 27 mg/m² (maximum dose of 59.4 mg; see note) IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16

Supportive therapy

• Dexamethasone (Decadron) as follows:
  • Cycle 1: 4 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, prior to carfilzomib
  • Cycle 2: 4 mg IV or PO once on day 1, prior to carfilzomib (Vij et al. 2012a only)
    • Restart dexamethasone premedication if patients experience infusion reactions: "fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina."
• "All patients were to receive oral and intravenous fluids before dosing to assure adequate hydration."

28-day cycle for up to 12 cycles

Dose and schedule modifications

• "Carfilzomib was withheld for grade 3 or 4 hematologic or nonhematologic toxicities and resumed at reduced doses of 15 mg/m² in cycle 1 or 20 mg/m² in cycle 2 and above on resolution."

Regimen variant #6, 20/56 dosing

Study	Dates of enrollment	Evidence	Efficacy
Papadopoulos et al. 2014 (PX-171-007)	2009-2013	Phase 1 (RT)
Lendvai et al. 2014 (MSK 10-228)	2011-2013	Phase 2	ORR: 55%

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once per day on days 1 & 2, then 56 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 56 mg/m² IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16

Supportive therapy

• Normal saline pre- and post-hydration, tapered over subsequent cycles (see text for details)
• Dexamethasone (Decadron) 8 mg (route not specified) mandated with each cycle 1 dose, then optional
• Palonosetron (Aloxi) 250 mcg (route not specified) mandated with each cycle 1 dose, then optional
• Acyclovir (Zovirax) 400 mg PO once per day

28-day cycles

References

1. PX-171-004 bortezomib-naive: Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, Kukreti V, Jagannath S, McDonagh KT, Alsina M, Bahlis NJ, Reu FJ, Gabrail NY, Belch A, Matous JV, Lee P, Rosen P, Sebag M, Vesole DH, Kunkel LA, Wear SM, Wong AF, Orlowski RZ, Siegel DS. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012 Jun 14;119(24):5661-70. Epub 2012 May 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00530816
2. PX-171-004 bortezomib-exposed: Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S, Wong AF, Wang M. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012 Sep;158(6):739-48. Epub 2012 Jul 30. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00530816
3. PX-171-003-A0: Jagannath S, Vij R, Stewart AK, Trudel S, Jakubowiak AJ, Reiman T, Somlo G, Bahlis N, Lonial S, Kunkel LA, Wong A, Orlowski RZ, Siegel DS. An open-label single-arm pilot phase II study (PX-171-003-A0) of low-dose, single-agent carfilzomib in patients with relapsed and refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):310-8. link to original article dosing details in abstract have been reviewed by our editors PubMed
4. PX-171-003-A1: Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. Epub 2012 Jul 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00511238
   1. Subgroup analysis: Jakubowiak AJ, Siegel DS, Martin T, Wang M, Vij R, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Harrison BL, Wong AF, Orlowski RZ, Jagannath S. Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013 Dec;27(12):2351-6. Epub 2013 May 14. link to original article link to PMC article PubMed
5. PX-171-005: Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00721734
6. MSK 10-228: Lendvai N, Hilden P, Devlin S, Landau H, Hassoun H, Lesokhin AM, Tsakos I, Redling K, Koehne G, Chung DJ, Schaffer WL, Giralt SA. A phase 2 single-center study of carfilzomib 56 mg/m² with or without low-dose dexamethasone in relapsed multiple myeloma. Blood. 2014 Aug 7;124(6):899-906. Epub 2014 Jun 24. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01351623
7. PX-171-007: Papadopoulos KP, Siegel DS, Vesole DH, Lee P, Rosen ST, Zojwalla N, Holahan JR, Lee S, Wang Z, Badros A. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015 Mar 1;33(7):732-9. Epub 2014 Sep 15. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00531284
8. Watanabe T, Tobinai K, Matsumoto M, Suzuki K, Sunami K, Ishida T, Ando K, Chou T, Ozaki S, Taniwaki M, Uike N, Shibayama H, Hatake K, Izutsu K, Ishikawa T, Shumiya Y, Kashihara T, Iida S. A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma. Br J Haematol. 2016 Mar;172(5):745-56. Epub 2016 Jan 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
9. FOCUS: Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01302392

Daratumumab monotherapy

Regimen variant #1

Study	Dates of enrollment	Evidence
Lokhorst et al. 2015 (GEN501 part 2)	2008 to not reported	Phase 1/2 (RT)
Lonial et al. 2016 (SIRIUS)	2013 to not reported	Phase 2 (RT)

Note: although SIRIUS was a randomized phase 2 trial, the randomization was to choose the dose for further assessment in an expansion cohort; the dose chosen (16 mg/kg from the start) is the one reported here:

Prior treatment criteria

• GEN501 part 2: 2 or more prior therapies, including immunomodulatory agents, proteasome inhibitors, chemotherapy, and autologous stem-cell transplantation
• SIRIUS: at least 3 lines of therapy including proteasome inhibitors and immunomodulatory drugs or refractory to both proteasome inhibitors and immunomodulatory drugs

Targeted therapy

• Daratumumab (Darzalex) as follows:
  • Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycles 3 & 4: 16 mg/kg IV once per day on days 1 & 15
  • Cycle 5 onwards: 16 mg/kg IV once on day 1
    • Note: Per the package insert, daratumumab infusion should complete within 15 hours. In Lokhorst et al. 2015, daratumumab was given over 8 hours.

Supportive therapy

This is a combination of what is listed in the daratumumab package insert and Lokhorst et al. 2015. There were protocol amendments in Lokhorst et al. 2015; listed medications are what was eventually used.

• Prior to all daratumumab infusions:
  • Methylprednisolone (Solumedrol) 100 mg IV once per infusion, prior to daratumumab
    • Per the package insert, after the second dose of daratumumab, dose may be reduced to 60 mg IV. Per Lokhorst et al. 2015, after the fourth dose of daratumumab, dose "could be reduced to 50 mg."
  • Acetaminophen (Tylenol) (paracetamol) 1000 mg (package insert: 650 to 1000 mg) PO once per infusion, 1 to 2 hours prior to daratumumab
  • One of the following antihistamines:
    • Clemastine (Tavist) 1 mg IV once per infusion, 1 to 2 hours prior to daratumumab
    • Cetirizine (Zyrtec) 10 mg PO once per infusion, 1 to 2 hours prior to daratumumab
    • Diphenhydramine (Benadryl) (or equivalent) 25 to 50 mg PO or IV once per infusion, 1 to 2 hours prior to daratumumab
• Post-treatment medications:
  • Methylprednisolone (Solumedrol) (or equivalent) 20 to 25 mg (package insert: 20 mg) PO once per day for two days after daratumumab
  • Package insert: "For patients with a history of obstructive pulmonary disorder, consider prescribing post-infusion medications such as short and long-acting bronchodilators, and inhaled corticosteroids."
• Package insert: "Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week of starting DARZALEX and continue for 3 months following treatment"

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mateos et al. 2020 (COLUMBA)	2017-10-31 to 2018-12-27	Phase 3 (C)	Daratumumab and hyaluronidase	Non-inferior ORR

Prior treatment criteria

• At least 3 lines of therapy including proteasome inhibitors and immunomodulatory drugs or refractory to both proteasome inhibitors and immunomodulatory drugs

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

28-day cycles

References

1. GEN501 part 2: Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, Minnema MC, Lassen U, Krejcik J, Palumbo A, van de Donk NW, Ahmadi T, Khan I, Uhlar CM, Wang J, Sasser AK, Losic N, Lisby S, Basse L, Brun N, Richardson PG. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. Epub 2015 Aug 26. link to original article dosing details in manuscript have been reviewed by our editors link to supplementary appendix link to study protocol PubMed NCT00574288
   1. Pooled update: Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. Epub 2016 May 23. link to original article link to PMC article PubMed
   2. Pooled update: Usmani SZ, Nahi H, Plesner T, Weiss BM, Bahlis NJ, Belch A, Voorhees PM, Laubach JP, van de Donk NWCJ, Ahmadi T, Uhlar CM, Wang J, Feng H, Qi M, Richardson PG, Lonial S. Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials. Lancet Haematol. 2020 Jun;7(6):e447-e455. link to original article PubMed
2. SIRIUS: Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, Belch A, Krishnan A, Vescio RA, Mateos MV, Mazumder A, Orlowski RZ, Sutherland HJ, Bladé J, Scott EC, Oriol A, Berdeja J, Gharibo M, Stevens DA, LeBlanc R, Sebag M, Callander N, Jakubowiak A, White D, de la Rubia J, Richardson PG, Lisby S, Feng H, Uhlar CM, Khan I, Ahmadi T, Voorhees PM. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. Epub 2016 Jan 7. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01985126
   1. Pooled update: Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, Lokhorst HM, Voorhees PM, Richardson PG, Chari A, Sasser AK, Axel A, Feng H, Uhlar CM, Wang J, Khan I, Ahmadi T, Nahi H. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. Epub 2016 May 23. link to original article link to PMC article PubMed
   2. Pooled update: Usmani SZ, Nahi H, Plesner T, Weiss BM, Bahlis NJ, Belch A, Voorhees PM, Laubach JP, van de Donk NWCJ, Ahmadi T, Uhlar CM, Wang J, Feng H, Qi M, Richardson PG, Lonial S. Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials. Lancet Haematol. 2020 Jun;7(6):e447-e455. link to original article PubMed
3. COLUMBA: Mateos MV, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis N, Flogegard M, Bladé J, Moreau P, Kaiser M, Iida S, Laubach J, Magen H, Cavo M, Hulin C, White D, De Stefano V, Clemens PL, Masterson T, Lantz K, O'Rourke L, Heuck C, Qin X, Parasrampuria DA, Yuan Z, Xu S, Qi M, Usmani SZ. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020 May;7(5):e370-e380. Epub 2020 Mar 23. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03277105
   1. Update: Usmani SZ, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis NJ, Flogegard M, Bladé J, Moreau P, Kaiser M, Iida S, Laubach J, Magen H, Cavo M, Hulin C, White D, De Stefano V, Lantz K, O'Rourke L, Heuck C, Delioukina M, Qin X, Nnane I, Qi M, Mateos MV. Final analysis of the phase 3 non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematologica. 2022 Oct 1;107(10):2408-2417. Epub 2022 Mar 31. link to original article link to PMC article PubMed

Daratumumab and hyaluronidase monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mateos et al. 2020 (COLUMBA)	2017-10-31 to 2018-12-27	Phase 3 (E-RT-switch-ic)	Daratumumab	Non-inferior ORR (co-primary endpoint) ORR: 41% vs 37% (RR 1.11, 95% CI 0.89-1.37)

Prior treatment criteria

• At least 3 lines of therapy including proteasome inhibitors and immunomodulatory drugs or refractory to both proteasome inhibitors and immunomodulatory drugs

Targeted therapy

• Daratumumab and hyaluronidase (Darzalex Faspro) as follows:
  • Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22
  • Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15
  • Cycle 7 onwards: 1800 mg SC once on day 1

28-day cycles

References

1. COLUMBA: Mateos MV, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis N, Flogegard M, Bladé J, Moreau P, Kaiser M, Iida S, Laubach J, Magen H, Cavo M, Hulin C, White D, De Stefano V, Clemens PL, Masterson T, Lantz K, O'Rourke L, Heuck C, Qin X, Parasrampuria DA, Yuan Z, Xu S, Qi M, Usmani SZ. Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial. Lancet Haematol. 2020 May;7(5):e370-e380. Epub 2020 Mar 23. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03277105
   1. Update: Usmani SZ, Nahi H, Legiec W, Grosicki S, Vorobyev V, Spicka I, Hungria V, Korenkova S, Bahlis NJ, Flogegard M, Bladé J, Moreau P, Kaiser M, Iida S, Laubach J, Magen H, Cavo M, Hulin C, White D, De Stefano V, Lantz K, O'Rourke L, Heuck C, Delioukina M, Qin X, Nnane I, Qi M, Mateos MV. Final analysis of the phase 3 non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma. Haematologica. 2022 Oct 1;107(10):2408-2417. Epub 2022 Mar 31. link to original article link to PMC article PubMed

Elranatamab monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Lesokhin et al. 2023 (MagnetisMM-3)	2021-02-09 to 2022-01-07	Phase 2 (RT)

Immunotherapy

• Elranatamab (Elrexfio) as follows:
  • Week 1: 12 mg SC once on day 1, then 32 mg SC once on day 4
  • Weeks 2 to 24: 76 mg SC once on day 1

7-day cycle for 24 cycles

Subsequent treatment

• MagnetisMM-3, PR or better and maintained response for at least 2 months: Elranatamab maintenance

References

1. MagnetisMM-3: Lesokhin AM, Tomasson MH, Arnulf B, Bahlis NJ, Miles Prince H, Niesvizky R, Rodrίguez-Otero P, Martinez-Lopez J, Koehne G, Touzeau C, Jethava Y, Quach H, Depaus J, Yokoyama H, Gabayan AE, Stevens DA, Nooka AK, Manier S, Raje N, Iida S, Raab MS, Searle E, Leip E, Sullivan ST, Conte U, Elmeliegy M, Czibere A, Viqueira A, Mohty M. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023 Sep;29(9):2259-2267. Epub 2023 Aug 15. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT04649359
   1. PRO analysis: Mohty M, Bahlis NJ, Nooka AK, DiBonaventura M, Ren J, Conte U. Impact of elranatamab on quality of life: Patient-reported outcomes from MagnetisMM-3. Br J Haematol. 2024 May;204(5):1801-1810. Epub 2024 Feb 29. link to original article PubMed

Idecabtagene vicleucel monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Raje et al. 2019 (CRB-401)	2016-2018	Phase 1, >20 pts
Munshi et al. 2021 (KarMMa)	2017-2018	Phase 2 (RT)
Rodriguez-Otero et al. 2023 (KarMMa-3)	2019-05 to 2022-04	Phase 3 (E-switch-ooc)	Investigator's choice of: 1a. Dara-Pd 1b. Dara-Vd 1c. IRd 1d. Kd 1e. Elo-Pd	Superior PFS (primary endpoint) Median PFS: 13.3 vs 4.4 mo (HR 0.49, 95% CI 0.38-0.65)

Preceding treatment

• FC lymphodepletion

Immunotherapy

• Idecabtagene vicleucel (Abecma) 150 x 10⁶ to 450 x 10⁶ CAR-positive T cells IV once on day 0

One course

References

1. CRB-401: Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, Liedtke M, Rosenblatt J, Maus MV, Turka A, Lam LP, Morgan RA, Friedman K, Massaro M, Wang J, Russotti G, Yang Z, Campbell T, Hege K, Petrocca F, Quigley MT, Munshi N, Kochenderfer JN. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019 May 2;380(18):1726-1737. link to original article link to PMC article PubMed NCT02658929
2. KarMMa: Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, Raje N, Lin Y, Siegel D, Oriol A, Moreau P, Yakoub-Agha I, Delforge M, Cavo M, Einsele H, Goldschmidt H, Weisel K, Rambaldi A, Reece D, Petrocca F, Massaro M, Connarn JN, Kaiser S, Patel P, Huang L, Campbell TB, Hege K, San-Miguel J. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Feb 25;384(8):705-716. link to original article PubMed NCT03361748
3. KarMMa-3: Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M, Giralt S. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023 Mar 16;388(11):1002-1014. Epub 2023 Feb 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03651128
   1. PRO analysis: Delforge M, Patel K, Eliason L, Dhanda D, Shi L, Guo S, Marshall TS, Arnulf B, Cavo M, Nooka A, Manier S, Callander N, Giralt S, Einsele H, Ailawadhi S, Popa McKiver M, Cook M, Rodríguez-Otero P. Health-related quality of life in patients with triple-class exposed relapsed and refractory multiple myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial. Lancet Haematol. 2024 Mar;11(3):e216-e227. link to original article PubMed

Ixazomib monotherapy

Regimen variant #1, bi-weekly, 2 out of 3 weeks

Study	Dates of enrollment	Evidence
Richardson et al. 2014 (C16003)	2009-2012	Phase 1/2

Note: this is the dosing used in the expansion cohort.

Targeted therapy

• Ixazomib (Ninlaro) 2 mg/m² PO once per day on days 1, 4, 8, 11

21-day cycle for up to 12 cycles

Regimen variant #2, 3 out of 4 weeks

Study	Dates of enrollment	Evidence
Kumar et al. 2015 (MC1181)	2012	Phase 2

Prior treatment criteria

• At least 1 prior line of therapy

Targeted therapy

• Ixazomib (Ninlaro) 5.5 mg PO once per day on days 1, 8, 15

28-day cycles

Subsequent treatment

• MC1181, patients with no minor response by end of cycle 2, no PR by end of cycle 4, or progression: Ixazomib & Dexamethasone

References

1. C16003: Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, Talpaz M, Berg D, Liu G, Yu J, Gupta N, Di Bacco A, Hui AM, Lonial S. Phase 1 study of twice-weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma patients. Blood. 2014 Aug 14;124(7):1038-46. Epub 2014 Jun 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00932698
2. MC1181: Kumar SK, LaPlant B, Roy V, Reeder CB, Lacy MQ, Gertz MA, Laumann K, Thompson MA, Witzig TE, Buadi FK, Rivera CE, Mikhael JR, Bergsagel PL, Kapoor P, Hwa L, Fonseca R, Stewart AK, Chanan-Khan A, Rajkumar SV, Dispenzieri A. Phase 2 trial of ixazomib in patients with relapsed multiple myeloma not refractory to bortezomib. Blood Cancer J. 2015 Aug 14;5:e338. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01415882

Lenalidomide monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2006	2002-2003	Randomized Phase 2 (E-switch-ic)	Lenalidomide; 15 mg PO twice per day	Did not meet primary endpoint of ORR
Richardson et al. 2009 (CC-5013-MM-014)	2003-2004	Phase 2

Note: This regimen is essentially of historical interest, as neither dosing of lenalidomide is in common use now.

Targeted therapy

• Lenalidomide (Revlimid) 30 mg PO once per day on days 1 to 21

28-day cycles

Subsequent treatment

• Richardson et al. 2006, patients with SD or progression after 2 cycles: Escalation to Rd

References

1. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
2. CC-5013-MM-014: Richardson P, Jagannath S, Hussein M, Berenson J, Singhal S, Irwin D, Williams SF, Bensinger W, Badros AZ, Vescio R, Kenvin L, Yu Z, Olesnyckyj M, Zeldis J, Knight R, Anderson KC. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009 Jul 23;114(4):772-8. Epub 2009 May 26. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00065351

Pomalidomide monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2014 (CC-4047-MM-002)	2009 to not reported	Randomized Phase 2 (C)	Pd	Inferior PFS

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.

Prior treatment criteria

• At least 2 lines of therapy including lenalidomide and bortezomib

Targeted therapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Supportive therapy

• Aspirin 81 to 100 mg PO once per day (unless contraindicated)

28-day cycles

References

1. CC-4047-MM-002: Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00833833

Talquetamab monotherapy

Regimen variant #1, weekly

FDA-recommended dose

Study	Dates of enrollment	Evidence
Chari et al. 2022 (MonumenTAL-1)	2018-01-03 to 2021-11-15	Phase 1b/2 (RT)

Note: this was one of two recommended phase 2 dose levels. Step-up dosing was used in the first week but the details are not clearly reported in the manuscript or in the appendix; the dosing here is from the Talvey website.

Immunotherapy

• Talquetamab (Talvey) as follows:
  • Step-up: 0.01 mg/kg SC once on day 1, then 0.06 mg/kg SC on day 4
  • Cycle 1 onwards: 0.4 mg/kg SC once on day 1

6-day course, then 7-day cycles

Regimen variant #2, bi-weekly

FDA-recommended dose

Study	Dates of enrollment	Evidence
Chari et al. 2022 (MonumenTAL-1)	2018-01-03 to 2021-11-15	Phase 1b/2 (RT)

Note: this was one of two recommended phase 2 dose levels. Step-up dosing was used in the first week but the details are not clearly reported in the manuscript or in the appendix; the dosing here is from the Talvey website.

Immunotherapy

• Talquetamab (Talvey) as follows:
  • Step-up: 0.01 mg/kg SC once on day 1, then 0.06 mg/kg SC on day 4, then 0.4 mg/kg SC on day 7
  • Cycle 1 onwards: 0.8 mg/kg SC once on day 1

9-day course, then 14-day cycles

References

1. MonumenTAL-1: Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk NWCJ, Rodríguez-Otero P, Askari E, Mateos MV, Costa LJ, Caers J, Verona R, Girgis S, Yang S, Goldsmith RB, Yao X, Pillarisetti K, Hilder BW, Russell J, Goldberg JD, Krishnan A. Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma. N Engl J Med. 2022 Dec 15;387(24):2232-2244. Epub 2022 Dec 10. link to original article contains partial dosing details in manuscript PubMed NCT03399799

Teclistamab monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Usmani et al. 2021 (MajesTEC-1 Phase 1)	2017-2021	Phase 1 (RT)
Moreau et al. 2022 (MajesTEC-1 Phase 2)	2020-2021	Phase 2 (RT)

Note: Phase 1 and phase 2 have different clinical trial ID's and are thus recorded separately; Moreau et al. 2022 is an update to the phase 1 portion and the first publication of the phase 2 results.

Immunotherapy

• Teclistamab (Tecvayli) as follows:
  • Cycle 1: 0.06 mg/kg SC once on day 1, then 0.3 mg/kg SC once on day 4, then 1.5 mg/kg SC once per day on days 8, 15, 22
  • Cycle 2 onwards: 1.5 mg/kg SC once per day on days 1, 8, 15, 22

28-day cycles

References

1. MajesTEC-1 Phase 1: Usmani SZ, Garfall AL, van de Donk NWCJ, Nahi H, San-Miguel JF, Oriol A, Rosinol L, Chari A, Bhutani M, Karlin L, Benboubker L, Pei L, Verona R, Girgis S, Stephenson T, Elsayed Y, Infante J, Goldberg JD, Banerjee A, Mateos MV, Krishnan A. Teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021 Aug 21;398(10301):665-674. Epub 2021 Aug 10. link to original article PubMed NCT03145181
   1. Update: Moreau P, Garfall AL, van de Donk NWCJ, Nahi H, San-Miguel JF, Oriol A, Nooka AK, Martin T, Rosinol L, Chari A, Karlin L, Benboubker L, Mateos MV, Bahlis N, Popat R, Besemer B, Martínez-López J, Sidana S, Delforge M, Pei L, Trancucci D, Verona R, Girgis S, Lin SXW, Olyslager Y, Jaffe M, Uhlar C, Stephenson T, Van Rampelbergh R, Banerjee A, Goldberg JD, Kobos R, Krishnan A, Usmani SZ. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022 Aug 11;387(6):495-505. Epub 2022 Jun 5. link to original article link to PMC article PubMed
2. MajesTEC-1 Phase 2: Moreau P, Garfall AL, van de Donk NWCJ, Nahi H, San-Miguel JF, Oriol A, Nooka AK, Martin T, Rosinol L, Chari A, Karlin L, Benboubker L, Mateos MV, Bahlis N, Popat R, Besemer B, Martínez-López J, Sidana S, Delforge M, Pei L, Trancucci D, Verona R, Girgis S, Lin SXW, Olyslager Y, Jaffe M, Uhlar C, Stephenson T, Van Rampelbergh R, Banerjee A, Goldberg JD, Kobos R, Krishnan A, Usmani SZ. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022 Aug 11;387(6):495-505. Epub 2022 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT04557098

Thalidomide monotherapy

Synopsis

Historical Background of Thalidomide

Originally developed and marketed in the late 1950s as a sedative and remedy for morning sickness in pregnant women, thalidomide led to catastrophic birth defects when taken during pregnancy. Due to these teratogenic effects, its usage was banned in many countries by the early 1960s.

Rediscovery and Anticancer Properties

During the late 1990s, the anti-angiogenic and immunomodulatory effects of thalidomide were explored. Researchers hypothesized that these properties could be harnessed against cancers that rely on angiogenesis.

Singhal et al., 1999 ([1] Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. New England Journal of Medicine. 1999;341:1565-71): This seminal study reported the effects of thalidomide in patients with refractory multiple myeloma. Thalidomide showed significant antitumor activity, leading to renewed interest in the drug.

Development of Analogues

The success of thalidomide spurred the development of its analogs, designed to retain its therapeutic benefits while minimizing side effects. Lenalidomide and pomalidomide are two such analogs that have shown significant efficacy in multiple myeloma with a better side effect profile.

Current Role in Therapy

While newer agents and combinations have emerged in the treatment landscape of multiple myeloma, thalidomide and its derivatives remain vital components in various treatment regimens, especially in certain settings and geographies.

Conclusion

The repositioning of thalidomide for multiple myeloma is a testament to the importance of re-evaluating existing drugs for new therapeutic indications. Its successful transition from a notorious drug to a vital component in the multiple myeloma treatment arsenal underscores the ever-evolving nature of drug development and therapy.
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
Singhal et al. 1999	1997-1998	Non-randomized

Targeted therapy

• Thalidomide (Thalomid) as follows:
  • Cycle 1: 200 mg PO once per day on days 1 to 14, then 400 mg PO once per day on days 15 to 28
  • Cycle 2: 600 mg PO once per day on days 1 to 14, then 800 mg PO once per day on days 15 to 28
  • Cycle 3 onwards: 800 mg PO once per day on days 1 to 28

28-day cycles

References

1. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeldis J, Siegel D, Crowley J, Barlogie B. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999 Nov 18;341(21):1565-71. Erratum in: N Engl J Med 2000 Feb 3;342(5):364. link to original article dosing details in abstract have been reviewed by our editors PubMed
2. Yakoub-Agha I, Mary JY, Hulin C, Doyen C, Marit G, Benboubker L, Voillat L, Moreau P, Berthou C, Stoppa AM, Maloisel F, Rodon P, Dib M, Pegourie B, Casassus P, Slama B, Damaj G, Zerbib R, Harousseau JL, Mohty M, Facon T; Intergroupe Francophone du Myélome (IFM). Low-dose vs. high-dose thalidomide for advanced multiple myeloma: a prospective trial from the Intergroupe Francophone du Myélome. Eur J Haematol. 2012 Mar;88(3):249-59. Epub 2012 Jan 4. link to original article PubMed

Vemurafenib monotherapy

Regimen

Study	Dates of enrollment	Evidence
Hyman et al. 2015 (VE-BASKET)	2012-2014	Phase 2, fewer than 20 pts in subgroup

Note: Andrulis et al. 2013 is a single patient case report with a good response. Sharman et al. reports two patients with good response. In the Hyman et al. 2015 trial, there were 5 patients with multiple myeloma; "No patients with multiple myeloma have had a response to date."

Targeted therapy

• Vemurafenib (Zelboraf) 960 mg PO twice per day

Continued indefinitely

References

1. Case report: Andrulis M, Lehners N, Capper D, Penzel R, Heining C, Huellein J, Zenz T, von Deimling A, Schirmacher P, Ho AD, Goldschmidt H, Neben K, Raab MS. Targeting the BRAF V600E mutation in multiple myeloma. Cancer Discov. 2013 Aug;3(8):862-9. Epub 2013 Apr 23. link to original article dosing details in abstract have been reviewed by our editors PubMed
2. Case series: Sharman JP, Chmielecki J, Morosini D, Palmer GA, Ross JS, Stephens PJ, Stafl J, Miller VA, Ali SM. Vemurafenib response in 2 patients with posttransplant refractory BRAF V600E-mutated multiple myeloma. Clin Lymphoma Myeloma Leuk. 2014 Oct;14(5):e161-3. Epub 2014 Jun 11. link to original article PubMed
3. VE-BASKET: Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, Wolf J, Raje NS, Diamond EL, Hollebecque A, Gervais R, Elez-Fernandez ME, Italiano A, Hofheinz RD, Hidalgo M, Chan E, Schuler M, Lasserre SF, Makrutzki M, Sirzen F, Veronese ML, Tabernero J, Baselga J. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015 Aug 20;373(8):726-36. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01524978

Venetoclax monotherapy

Regimen

Study	Dates of enrollment	Evidence
Kumar et al. 2017 (M13-367)	2012 to not reported	Phase 1, >20 pts in this cohort

Note: This is the safety expansion cohort dosing.

Biomarker eligibility criteria

• t(11;14)

Targeted therapy

• Venetoclax (Venclexta) as follows:
  • Lead-in: 400 mg PO once per day on days 1 to 7, then 800 mg PO once per day on days 8 to 14
  • Cycle 1 onwards: 1200 mg PO once per day on days 1 to 21

14-day lead-in, then 21-day cycles

References

1. M13-367: Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, Benboubker L, Facon T, Amiot M, Moreau P, Punnoose EA, Alzate S, Dunbar M, Xu T, Agarwal SK, Enschede SH, Leverson JD, Ross JA, Maciag PC, Verdugo M, Touzeau C. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017 Nov 30;130(22):2401-2409. Epub 2017 Oct 10. link to original article dosing details in supplement have been reviewed by our editors PubMed NCT01794520

Relapsed or refractory, doublets

Bortezomib & Dexamethasone (Vd)

Vd: Velcade (Bortezomib) & low-dose dexamethasone
BD: Bortezomib & Dexamethasone
Bd: Bortezomib & low-dose dexamethasone
Bort-Dex: Bortezomib & Dexamethasone

Regimen variant #1, indefinite 21-day then 28-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jakubowiak et al. 2016 (CA204-009)	2012-2013	Randomized Phase 2 (C)	Elo-Vd	Might have inferior PFS
Kumar et al. 2020 (BELLINI)	2016-07-19 to 2017-10-31	Phase 3 (C)	Vd & Venetoclax	Inferior PFS1 Median PFS: 11.5 vs 22.4 mo (HR 1.59, 95% CI 1.11-2.27)

¹Despite meeting the primary endpoint, there was increased mortality in the experimental group, due to increased infections.

Prior treatment criteria

• CA204-009 & BELLINI: 1 to 3 prior lines of therapy

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² IV or SC once per day on days 1, 4, 8, 11
  • Cycle 9 onwards: 1.3 mg/m² IV or SC once per day on days 1, 8, 15

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycle 9 onwards: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16

21-day cycle for 8 cycles, then 28-day cycles

Regimen variant #2, SC 21-day cycles (8 total)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moreau et al. 2011 (MMY-3021)	2008-2010	Phase 3 (E-RT-switch-ic)	Bort-Dex; IV	Non-inferior ORR after 4 cycles (primary endpoint) ORR after 4 cycles: 42% vs 42%
Terpos et al. 2017 (OPTIMRETREAT)	2013-2016	Phase 3 (C)	Bort-Dex x 6, then bortezomib maint.	Did not meet primary endpoint of PFS
Palumbo et al. 2016 (CASTOR)	2014-09-04 to 2015-09-24	Phase 3 (C)	Dara-Vd	Inferior OS1
Lu et al. 2021 (LEPUS)	2017-2019	Phase 3 (C)	Dara-Vd	Inferior PFS (primary endpoint)

¹Reported efficacy for CASTOR is based on the 2022 update.
Note: In MMY-3021, patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles.

Prior treatment criteria

• MMY-3021: 1 to 3 prior lines of therapy
• CASTOR: At least 1 prior line of therapy

Preceding treatment

• MMY-3021: Bortezomib x 4

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles (see note)

Regimen variant #3, IV 21-day cycles (16 total)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
San-Miguel et al. 2014 (PANORAMA 1)	2010-2012	Phase 3 (C)	Vd & Panobinostat	Inferior PFS

Note: Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to the last 8 cycles.

Prior treatment criteria

• 1 to 3 prior lines of therapy

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² IV once per day on days 1, 4, 8, 11
  • Cycles 9 to 16: 1.3 mg/m² IV once per day on days 1 & 8

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 9 to 16: 20 mg PO once per day on days 1, 2, 8, 9

21-day cycle for 16 cycles

Regimen variant #4, 21-day cycles, response-adapted

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hjorth et al. 2012 (NMSG 17/07)	2007-2010	Phase 3 (E-switch-ooc)	Thal-Dex	Did not meet primary endpoint of PFS
Dimopoulos et al. 2013 (CR013165)	2008-2009	Phase 2	Not evaluable

Prior treatment criteria

• NMSG 17/07: Failure of melphalan with no prior exposure to bortezomib or thalidomide
• CR013165: 1 prior line of therapy

Targeted therapy

• 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

Supportive therapy

• "Antithrombotic prophylaxis and acyclovir prophylaxis were not mandatory according to the study protocol but used routinely in an increasing proportion of participating centers during the study period."

21-day cycles until progression or best response, which would then be followed by 1 to 2 additional cycles

Regimen variant #5, IV 21-day cycles (8 total)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jagannath et al. 2004 (CREST)	2001-2002	Randomized Phase 2 (E-esc)	Bort-Dex; low-dose	Did not meet primary endpoint of ORR
Moreau et al. 2011 (MMY-3021)	2008-2010	Phase 3 (C)	Bort-Dex; SC	Non-inferior ORR after 4 cycles (primary endpoint)
Kropff et al. 2017 (CR015247)	2008-2010	Phase 3 (C)	VCD	Did not meet primary endpoint of TTP

Note: In MMY-3021, patients who were "evolving" towards CR after 8 cycles could receive 2 additional cycles.

Prior treatment criteria

• CREST: Failure of frontline chemotherapy
• MMY-3021 & CR015247: 1 to 3 prior lines of therapy

Preceding treatment

• CREST: Bortezomib x 2 to 4 cycles
• MMY-3021: Bortezomib x 4

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus 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 (see note)

Regimen variant #6, low-dose IV 21-day cycles (8 total)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jagannath et al. 2004 (CREST)	2001-2002	Randomized Phase 2 (E-de-esc)	Bort-Dex; standard-dose	Did not meet primary endpoint of ORR

Prior treatment criteria

• CREST: Failure of frontline chemotherapy

Preceding treatment

• Bortezomib x 2 to 4 cycles

Targeted therapy

• Bortezomib (Velcade) 1 mg/m² IV bolus 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

Regimen variant #7, IV indefinite 21-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2003 (SUMMIT)	2001-02 to 2001-12	Phase 2 (RT)		RR: 35%
Dimopoulos et al. 2015 (ENDEAVOR)	2012-06-20 to 2014-06-30	Phase 3 (C)	Kd	Inferior OS1

¹Reported efficacy for ENDEAVOR is based on the 2019 update.
Note: SUMMIT & MMY-3001 specified a total of 8 cycles, but those who were deriving clinical benefit could continue beyond this.

Prior treatment criteria

• ENDEAVOR: 1 to 3 prior lines of therapy

Preceding treatment

• SUMMIT & MMY-3001: Bortezomib x 2 to 4 cycles

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycles

Regimen variant #8, SC indefinite 21-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2015 (ENDEAVOR)	2012-06-20 to 2014-06-30	Phase 3 (C)	Kd	Inferior OS1

¹Reported efficacy for ENDEAVOR is based on the 2019 update.

Prior treatment criteria

• ENDEAVOR: 1 to 3 prior lines of therapy

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 4, 8, 11

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycles

Regimen variant #9, SC indefinite 21-day then 35-day cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Grosicki et al. 2020 (BOSTON)	2017-2019	Phase 3 (C)	SVd	Inferior PFS

Prior treatment criteria

• 1 to 3 prior lines of therapy, including proteasome inhibitors

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² SC once per day on days 1, 4, 8, 11
  • Cycle 9 onwards: 1.3 mg/m² SC once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycle 9 onwards: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23, 29, 30

21-day cycle for 8 cycles, then 35-day cycles

Regimen variant #10, indefinite 35-day cycles

Study	Dates of enrollment	Evidence	Efficacy
Fukushima et al. 2011	2007-2010	Retrospective	ORR: 77%

Note: treatment could be stopped if CR was achieved.

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

35-day cycles

References

1. SUMMIT: Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   1. Subgroup analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article dosing details in abstract have been reviewed by our editors PubMed
   2. Pooled subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article PubMed
2. CREST: Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004 Oct;127(2):165-72. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   1. Subgroup analysis: Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006 Jul;91(7):929-34. link to original article dosing details in abstract have been reviewed by our editors PubMed
   2. Update: Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Esseltine DL, Anderson KC. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008 Nov;143(4):537-40. Epub 2008 Sep 6. link to original article PubMed
3. MMY-3001: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00103506
   1. Update: Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   2. Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article link to PMC article PubMed
4. MMY-3021: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. Epub 2011 Apr 18. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00722566
   1. Update: Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, van de Velde H, Feng H, Cakana A, Deraedt W, Moreau P. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012 Dec;97(12):1925-8. Epub 2012 Jun 11. link to original article link to PMC article PubMed
   2. Subgroup analysis: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Rekhtman G, Masliak Z, Robak P, Esseltine DL, Feng H, Deraedt W, van de Velde H, Arnulf B. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study. Haematologica. 2015 May;100(5):e207-10. Epub 2015 Jan 16. link to original article link to PMC article PubMed
5. Retrospective: Fukushima T, Nakamura T, Iwao H, Nakajima A, Miki M, Sato T, Sakai T, Sawaki T, Fujita Y, Tanaka M, Masaki Y, Nakajima H, Motoo Y, Umehara H. Efficacy and safety of bortezomib plus dexamethasone therapy for refractory or relapsed multiple myeloma: once-weekly administration of bortezomib may reduce the incidence of gastrointestinal adverse events. Anticancer Res. 2011 Jun;31(6):2297-302. link to original article dosing details in manuscript have been reviewed by our editors PubMed
6. NMSG 17/07: Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group. Thalidomide and dexamethasone vs bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00602511
7. CR013165: Dimopoulos MA, Beksac M, Benboubker L, Roddie H, Allietta N, Broer E, Couturier C, Mazier MA, Angermund R, Facon T. Phase 2 study of bortezomib-dexamethasone alone or with added cyclophosphamide or lenalidomide for sub-optimal response as second-line treatment for patients with multiple myeloma. Haematologica. 2013 Aug;98(8):1264-72. Epub 2013 May 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00908232
8. PANORAMA 1: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01023308
   1. Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article link to PMC article PubMed
   2. Update: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. Epub 2016 Oct 14. link to original article PubMed
9. ENDEAVOR: Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. link to original article PubMed NCT01568866
   1. Subgroup analysis: Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. Epub 2016 Dec 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
   2. Update: Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. Epub 2017 Aug 23. link to original article PubMed
   3. Update: Orlowski RZ, Moreau P, Niesvizky R, Ludwig H, Oriol A, Chng WJ, Goldschmidt H, Yang Z, Kimball AS, Dimopoulos M. Carfilzomib-Dexamethasone Versus Bortezomib-Dexamethasone in Relapsed or Refractory Multiple Myeloma: Updated Overall Survival, Safety, and Subgroups. Clin Lymphoma Myeloma Leuk. 2019 Aug;19(8):522-530.e1. Epub 2019 May 2. link to original article PubMed
10. CA204-009: Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. link to original article dosing details in supplement have been reviewed by our editors link to PMC article PubMed NCT01478048
11. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix dosing details in manuscript have been reviewed by our editors PubMed NCT02136134
    1. Update: Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, Masszi T, Lauri B, Levin MD, Bosi A, Hungria V, Cavo M, Lee JJ, Nooka AK, Quach H, Lee C, Barreto W, Corradini P, Min CK, Scott EC, Chanan-Khan AA, Horvath N, Capra M, Beksac M, Ovilla R, Jo JC, Shin HJ, Sonneveld P, Soong D, Casneuf T, Chiu C, Amin H, Qi M, Thiyagarajah P, Sasser AK, Schecter JM, Mateos MV. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018 Dec;103(12):2079-87. Epub 2018 Sep 20. link to original article link to PMC article PubMed
    2. Update: Mateos MV, Sonneveld P, Hungria V, Nooka AK, Estell JA, Barreto W, Corradini P, Min CK, Medvedova E, Weisel K, Chiu C, Schecter JM, Amin H, Qin X, Ukropec J, Kobos R, Spencer A. Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR. Clin Lymphoma Myeloma Leuk. 2020 Aug;20(8):509-518. Epub 2019 Oct 9. link to original article PubMed
    3. Update: Sonneveld P, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Levin MD, Ahmadi T, Qin X, Garvin Mayo W, Gai X, Carey J, Carson R, Spencer A. Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2023 Mar 10;41(8):1600-1609. Epub 2022 Nov 22. link to original article link to PMC article PubMed
12. CR015247: Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. Epub 2017 Sep 14. link to original article PubMed NCT00813150
13. OPTIMRETREAT: Terpos E, Gobbi M, Potamianou A, Lahaye M, Couturier C, Cavo M. Retreatmentvand prolonged therapy with subcutaneous bortezomib in patients with relapsed multiple myeloma: a randomized, controlled, phase III study. Eur J Haematol. 2018 Jan;100(1):10-19. Epub 2017 Oct 30. link to original article PubMed NCT01910987
14. BELLINI: Kumar SK, Harrison SJ, Cavo M, de la Rubia J, Popat R, Gasparetto C, Hungria V, Salwender H, Suzuki K, Kim I, Punnoose EA, Hong WJ, Freise KJ, Yang X, Sood A, Jalaluddin M, Ross JA, Ward JE, Maciag PC, Moreau P. Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2020 Dec;21(12):1630-1642. Epub 2020 Oct 29. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02755597
15. BOSTON: Grosicki S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, Pylypenko H, Auner HW, Leleu X, Doronin V, Usenko G, Bahlis NJ, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Gironella M, Jurczyszyn A, Robak P, Galli M, Wallington-Beddoe C, Radinoff A, Salogub G, Stevens DA, Basu S, Liberati AM, Quach H, Goranova-Marinova VS, Bila J, Katodritou E, Oliynyk H, Korenkova S, Kumar J, Jagannath S, Moreau P, Levy M, White D, Gatt ME, Facon T, Mateos MV, Cavo M, Reece D, Anderson LD Jr, Saint-Martin JR, Jeha J, Joshi AA, Chai Y, Li L, Peddagali V, Arazy M, Shah J, Shacham S, Kauffman MG, Dimopoulos MA, Richardson PG, Delimpasi S. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020 Nov 14;396(10262):1563-1573. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03110562
16. LEPUS: Lu J, Fu W, Li W, Hu J, An G, Wang Y, Fu C, Chen L, Jin J, Cen X, Ge Z, Cai Z, Niu T, Qi M, Sun S, Gai X, Liu W, Liu W, Yang X, Huang X. Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study. Clin Lymphoma Myeloma Leuk. 2021 Sep;21(9):e699-e709. Epub 2021 Apr 24. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03234972
17. BENCH: NCT04939142
18. Perifosine 339: NCT01002248

Bortezomib & Pegylated liposomal doxorubicin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Orlowski et al. 2007 (MMY-3001)	2004-2006	Phase 3 (E-RT-esc)	Bortezomib	Superior TTP (primary endpoint) Median TTP: 9.3 vs 6.5 mo (HR 0.55, 95% CI 0.43-0.71)

Prior treatment criteria

• 1 to 3 prior lines of therapy, not including bortezomib

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 30 mg/m² IV over at least 1 hour once on day 4, given second

Supportive therapy

• Bisphosphonates were used according to established guidelines

21-day cycle for 8 or more cycles

References

1. MMY-3001: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1;25(25):3892-901. Epub 2007 Aug 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00103506
   1. Update: Mikhael JR, Belch AR, Prince HM, Lucio MN, Maiolino A, Corso A, Petrucci MT, Musto P, Komarnicki M, Stewart AK. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program. Br J Haematol. 2009 Jan;144(2):169-75. Epub 2008 Nov 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed
   2. Update: Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Xiu L, Cakana A, Parekh T, San-Miguel JF. Final overall survival results of a randomized trial comparing bortezomib plus pegylated liposomal doxorubicin with bortezomib alone in patients with relapsed or refractory multiple myeloma. Cancer. 2016 Jul 1;122(13):2050-6. Epub 2016 May 18. link to original article link to PMC article PubMed

Bortezomib & Vorinostat

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2013 (VANTAGE 088)	2008-2011	Phase 3 (E-esc)	Bortezomib	Superior PFS (primary endpoint) Median PFS: 7.6 vs 6.8 mo (HR 0.77, 95% CI 0.64-0.94)

Prior treatment criteria

• 1 to 3 prior lines of therapy

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
• Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 14

21-day cycles

References

1. VANTAGE 088: Dimopoulos M, Siegel DS, Lonial S, Qi J, Hajek R, Facon T, Rosinol L, Williams C, Blacklock H, Goldschmidt H, Hungria V, Spencer A, Palumbo A, Graef T, Eid JE, Houp J, Sun L, Vuocolo S, Anderson KC. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013 Oct;14(11):1129-1140. Epub 2013 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00773747

Carfilzomib & Dexamethasone (Kd)

Kd: Kyprolis (Carfilzomib) & low-dose dexamethasone

Regimen variant #1, 20/27

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moreau et al. 2018 (ARROWMM)	2015-09 to 2016-08	Phase 3 (C)	Kd; weekly	Inferior PFS

Note: this trial is denoted as ARROW_MM to distinguish from other trials of the same name.

Prior treatment criteria

• 2 or 3 lines of therapy, including a proteasome inhibitor and an immunomodulatory agent

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 10 minutes once per day on days 1 & 2, then 27 mg/m² IV over 10 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 40 mg IV or PO once per day on days 1, 8, 15, 22
  • Cycle 10 onwards: 40 mg IV or PO once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 20/56 dosing

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2015 (ENDEAVOR)	2012-06-20 to 2014-06-30	Phase 3 (E-RT-switch-ic)	Vd	Superior OS1 (secondary endpoint) Median OS: 47.8 vs 38.8 mo (HR 0.76, 95% CI 0.63-0.92) Superior PFS (primary endpoint) Median PFS: 18.7 vs 9.4 mo (HR 0.53, 95% CI 0.44-0.65)
Dimopoulos et al. 2020 (CANDOR)	2017-06-13 to 2018-06-25	Phase 3 (C)	Dara-Kd	Inferior PFS
Moreau et al. 2021 (IKEMA)	2017-11-15 to 2019-03-21	Phase 3 (C)	Isa-Kd	Inferior PFS
Rodriguez-Otero et al. 2023 (KarMMa-3)	2019-05 to 2022-04	Phase 3 (C)	Ide-cel	Inferior PFS

¹Reported efficacy for ENDEAVOR is based on the 2019 update.
Note: Some references mention using dexamethasone 40 mg on day 22. In KarMMA-3, the day 22 dexamethasone was split into 20 mg on days 22 & 23; the total dose per cycle is the same.

Prior treatment criteria

• ENDEAVOR & IKEMA: 1 to 3 prior lines of therapy

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once per day on days 1 & 2, then 56 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 56 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles

Regimen variant #3, 20/70 dosing (weekly)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Berenson et al. 2016 (CHAMPION-1)	2012-2014	Phase 1/2
Moreau et al. 2018 (ARROWMM)	2015-09 to 2016-08	Phase 3 (E-RT-switch-ic)	Kd; twice-weekly	Superior PFS (primary endpoint) Median PFS: 11.2 vs 7.6 mo (HR 0.69, 95% CI 0.54-0.83)

Note: this trial is denoted as ARROW_MM to distinguish from other trials of the same name.

Prior treatment criteria

• ARROW_MM: 2 or 3 lines of therapy, including a proteasome inhibitor and an immunomodulatory agent

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once on day 1, then 70 mg/m² IV over 30 minutes once per day on days 8 & 15
  • Cycle 2 onwards: 70 mg/m² IV over 30 minutes once per day on days 1, 8, 15

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 40 mg IV or PO once per day on days 1, 8, 15, 22
  • Cycle 10 onwards: 40 mg IV or PO once per day on days 1, 8, 15

28-day cycles

Regimen variant #4, 27 dosing

Study	Dates of enrollment	Evidence
Badros et al. 2013 (PX-171-005)	2008-2010	Phase 2

Preceding treatment

• Carfilzomib x 2 to 4 cycles (carfilzomib dose escalation attained during this period)

Targeted therapy

• Carfilzomib (Kyprolis) 27 mg/m² IV over 2 to 10 minutes once per day on days 1, 2, 8, 9, 15, 16

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg (route not specified) once per day on days 1, 2, 8, 9, 15, 16, given first

28-day cycle for 12 cycles or longer if deriving clinical benefit

References

1. PX-171-005: Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, Lee S, Wong AF, Niesvizky R. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013 Aug;27(8):1707-14. Epub 2013 Jan 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00721734
2. ENDEAVOR: Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosiñol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. Epub 2015 Dec 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01568866
   1. Subgroup analysis: Chng WJ, Goldschmidt H, Dimopoulos MA, Moreau P, Joshua D, Palumbo A, Facon T, Ludwig H, Pour L, Niesvizky R, Oriol A, Rosiñol L, Suvorov A, Gaidano G, Pika T, Weisel K, Goranova-Marinova V, Gillenwater HH, Mohamed N, Feng S, Aggarwal S, Hájek R. Carfilzomib-dexamethasone vs bortezomib-dexamethasone in relapsed or refractory multiple myeloma by cytogenetic risk in the phase 3 study ENDEAVOR. Leukemia. 2017 Jun;31(6):1368-1374. Epub 2016 Dec 27. link to original article link to PMC article PubMed
   2. Update: Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1327-1337. Epub 2017 Aug 23. link to original article PubMed
   3. Update: Orlowski RZ, Moreau P, Niesvizky R, Ludwig H, Oriol A, Chng WJ, Goldschmidt H, Yang Z, Kimball AS, Dimopoulos M. Carfilzomib-Dexamethasone Versus Bortezomib-Dexamethasone in Relapsed or Refractory Multiple Myeloma: Updated Overall Survival, Safety, and Subgroups. Clin Lymphoma Myeloma Leuk. 2019 Aug;19(8):522-530.e1. Epub 2019 May 2. link to original article PubMed
3. CHAMPION-1: Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016 Jun 30;127(26):3360-8. Epub 2016 May 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01677858
4. ARROW_MM: Moreau P, Mateos MV, Berenson JR, Weisel K, Lazzaro A, Song K, Dimopoulos MA, Huang M, Zahlten-Kumeli A, Stewart AK. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (ARROW): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018 Jul;19(7):953-964. Epub 2018 Jun 1. Erratum in: Lancet Oncol. 2018 Aug;19(8):e382. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02412878
5. CANDOR: Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Yang H, Klippel Z, Zahlten-Kumeli A, Usmani SZ. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020 Jul 18;396(10245):186-197. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03158688
   1. Update: Usmani SZ, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Gavriatopoulou M, Oriol A, Rabin N, Nooka A, Qi M, Beksac M, Jakubowiak A, Ding B, Zahlten-Kumeli A, Yusuf A, Dimopoulos M. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022 Jan;23(1):65-76. Epub 2021 Dec 3. link to original article PubMed
6. IKEMA: Moreau P, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Risse ML, Asset G, Macé S, Martin T; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021 Jun 19;397(10292):2361-2371. Epub 2021 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03275285
   1. Update: Martin T, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Casca F, Macé S, Risse ML, Moreau P. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. 2023 May 9;13(1):72. Erratum in: Blood Cancer J. 2023 Sep 27;13(1):152. link to original article link to PMC article PubMed
   2. Update: Yong K, Martin T, Dimopoulos MA, Mikhael J, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Casca F, Macé S, Risse ML, Moreau P. Isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma (IKEMA): overall survival analysis of a phase 3, randomised, controlled trial. Lancet Haematol. 2024 Oct;11(10):e741-e750. Epub 2024 Jul 24. link to original article PubMed
7. KarMMa-3: Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M, Giralt S. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023 Mar 16;388(11):1002-1014. Epub 2023 Feb 10. link to original article dosing details in supplement have been reviewed by our editors PubMed NCT03651128
   1. PRO analysis: Delforge M, Patel K, Eliason L, Dhanda D, Shi L, Guo S, Marshall TS, Arnulf B, Cavo M, Nooka A, Manier S, Callander N, Giralt S, Einsele H, Ailawadhi S, Popa McKiver M, Cook M, Rodríguez-Otero P. Health-related quality of life in patients with triple-class exposed relapsed and refractory multiple myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial. Lancet Haematol. 2024 Mar;11(3):e216-e227. link to original article PubMed

Carfilzomib & Panobinostat

Regimen

Study	Dates of enrollment	Evidence
Berdeja et al. 2015 (SCRI MM 27)	2012-2013	Phase 2

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1 & 2, then 45 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 45 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
• Panobinostat (Farydak) 30 mg PO once per day on days 1, 3, 5, 15, 17, 19

28-day cycles

References

1. SCRI MM 27: Berdeja JG, Hart LL, Mace JR, Arrowsmith ER, Essell JH, Owera RS, Hainsworth JD, Flinn IW. Phase I/II Study of the Combination of Panobinostat and Carfilzomib in Patients with Relapsed/Refractory Multiple Myeloma. Haematologica. 2015 May;100(5):670-6. Epub 2015 Feb 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01496118

Cyclophosphamide & Dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hájek et al. 2016 (FOCUS)	2010-2012	Phase 3 (C)	Carfilzomib	Did not meet primary endpoint of OS

Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Prior treatment criteria

• At least 3 lines of therapy including bortezomib, lenalidomide or thalidomide, an alkylating agent, and corticosteroids

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day

Glucocorticoid therapy

• Dexamethasone (Decadron) 6 mg PO once every other day

Continued indefinitely

References

1. FOCUS: Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01302392

Cyclophosphamide & Prednisone

CP: Cyclophosphamide & Prednisone
CyPred: Cyclophosphamide & Prednisone

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hájek et al. 2016 (FOCUS)	2010-2012	Phase 3 (C)	Carfilzomib	Did not meet primary endpoint of OS

Note: cyclophosphamide was described as optional for the control arm but 95% of patients received it. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Prior treatment criteria

• At least 3 lines of therapy including bortezomib, lenalidomide or thalidomide, an alkylating agent, and corticosteroids

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day

Glucocorticoid therapy

• Prednisone (Sterapred) 30 mg PO once every other day

Continued indefinitely

Regimen variant #2

Study	Dates of enrollment	Evidence
de Weerdt et al. 2001	1991-1998	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg PO once per day

Glucocorticoid therapy

• Prednisone (Sterapred) 10 to 20 mg PO once per day

Continued indefinitely

References

1. de Weerdt O, van de Donk NW, Veth G, Bloem AC, Hagenbeek A, Lokhorst HM. Continuous low-dose cyclophosphamide-prednisone is effective and well tolerated in patients with advanced multiple myeloma. Neth J Med. 2001 Aug;59(2):50-6. link to original article dosing details in abstract have been reviewed by our editors PubMed
2. FOCUS: Hájek R, Masszi T, Petrucci MT, Palumbo A, Rosiñol L, Nagler A, Yong KL, Oriol A, Minarik J, Pour L, Dimopoulos MA, Maisnar V, Rossi D, Kasparu H, Van Droogenbroeck J, Yehuda DB, Hardan I, Jenner M, Calbecka M, Dávid M, de la Rubia J, Drach J, Gasztonyi Z, Górnik S, Leleu X, Munder M, Offidani M, Zojer N, Rajangam K, Chang YL, San-Miguel JF, Ludwig H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia. 2017 Jan;31(1):107-114. Epub 2016 Jun 24. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01302392

Ixazomib & Dexamethasone

Regimen variant #1, 4/20

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kumar et al. 2015 (MC1181 part 2)	2013-2015	Randomized Phase 2 (E-de-esc)	Ixazomib & Dexamethasone; 5.5 mg/20 mg	Might have inferior ORR (primary endpoint)

Prior treatment criteria

• At least 1 prior line of therapy

Targeted therapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16

Supportive therapy

• Herpes zoster prophylaxis

28-day cycles

Regimen variant #2, 5.5/20

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kumar et al. 2015 (MC1181 part 2)	2013-2015	Randomized Phase 2 (E-esc)	Ixazomib & Dexamethasone; 4 mg/20 mg	Might have superior ORR (primary endpoint)

Prior treatment criteria

• At least 1 prior line of therapy

Targeted therapy

• Ixazomib (Ninlaro) 5.5 mg PO once per day on days 1, 8, 15

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16

Supportive therapy

• Herpes zoster prophylaxis

28-day cycles

References

1. MC1181 part 2: Kumar SK, LaPlant BR, Reeder CB, Roy V, Halvorson AE, Buadi F, Gertz MA, Bergsagel PL, Dispenzieri A, Thompson MA, Crawley J, Kapoor P, Mikhael J, Stewart K, Hayman SR, Hwa YL, Gonsalves W, Witzig TE, Ailawadhi S, Dingli D, Go RS, Lin Y, Rivera CE, Rajkumar SV, Lacy MQ. Randomized phase 2 trial of ixazomib and dexamethasone in relapsed multiple myeloma not refractory to bortezomib. Blood. 2016 Nov 17;128(20):2415-2422. Epub 2016 Oct 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01415882

Lenalidomide & Dexamethasone (Rd)

Rd: Revlimid (Lenalidomide) & low-dose dexamethasone
RevDex: Revlimid (Lenalidomide) & Dexamethasone
Ld: Lenalidomide & low-dose dexamethasone
LenDex: Lenalidomide & Dexamethasone

Regimen variant #1, Len @ 25 mg 21/28

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Stewart et al. 2014 (ASPIRE)	2010-2012	Phase 3 (C)	KRd	Inferior OS1	Inferior GHS/QoL
Goldschmidt et al. 2020 (ReLApsE)	2010-2016	Phase 3 (C)	Rd x 3, then Melphalan auto HSCT, then Lenalidomide	Did not meet primary endpoint of PFS
Lonial et al. 2015 (ELOQUENT-2)	2011-06 to 2012-11	Phase 3 (C)	Elo-Rd	Seems to have inferior OS2
Moreau et al. 2016 (TOURMALINE-MM1)	2012-2014	Phase 3 (C)	IRd	Inferior PFS
Dimopoulos et al. 2016 (POLLUX)	2014-06-16 to 2015-07-14	Phase 3 (C)	Dara-Rd	Inferior OS3
Hou et al. 2017 (TOURMALINE-MM1 China Continuation)	2014-05-08 to 2015-05-08	Phase 3 (C)	IRd	Inferior OS

¹Reported efficacy for ASPIRE is based on the 2018 update.
²Reported efficacy for ELOQUENT-2 is based on the 2020 update.
³Reported efficacy for POLLUX is based on the 2023 update.

Prior treatment criteria

• ASPIRE, ReLApsE, ELOQUENT-2, TOURMALINE-MM1, POLLUX, TOURMALINE-MM1 China Continuation: 1 to 3 prior lines of therapy

Targeted therapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
  • POLLUX: Patients with CrCl of 30 to 60 mL/min/1.73m² received 10 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
  • POLLUX: Patients older than 75 years or underweight (BMI less than 18.5) could receive 20 mg

Supportive therapy

Best described by ASPIRE:

• Valacyclovir (Valtrex) (dose not specified) or equivalent antiviral while taking Lenalidomide (Revlimid)
• Aspirin (dose not specified) or other anticoagulant or antiplatelet medication such as Clopidogrel (Plavix), low-molecular-weight heparin or Warfarin (Coumadin) while taking Lenalidomide (Revlimid)
• Bisphosphonates while taking Dexamethasone (Decadron)
• Lansoprazole (Prevacid) (dose not specified) or other proton pump inhibitor while taking Dexamethasone (Decadron)
• A prophylactic antibiotic (Ciprofloxacin (Cipro), Amoxicillin, Trimethoprim-Sulfamethoxazole (Bactrim DS) are given as examples)

28-day cycles

Regimen variant #2, Len @ 25 mg 21/28, with high-dose dex lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Weber et al. 2007 (MM-009)	2003-02-27 to 2004-04-14	Phase 3 (E-RT-esc)	Dexamethasone	Seems to have superior OS1 (secondary endpoint) Superior TTP (primary endpoint) Median TTP: 11.1 vs 4.7 mo (HR 0.35, 95% CI 0.27-0.47)
Dimopoulos et al. 2007 (MM-010)	2003-09-22 to 2004-09-15	Phase 3 (E-RT-esc)	Dexamethasone	Seems to have superior OS (secondary endpoint) Median OS: NYR vs 20.6 mo (HR 0.66, 95% CI 0.45-0.96) Superior TTP (primary endpoint) Median TTP: 11.3 vs 4.7 mo (HR 0.35, 95% CI 0.27-0.46)

¹Reported efficacy of MM-009 is based on the 2009 pooled update.
Note: MM-009 is "Study 1" and MM-010 is "Study 2" listed in the package insert.

Prior treatment criteria

• MM-009 & MM-010: At least 1 prior line of therapy

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

28-day cycles

Regimen variant #3, Len @ 15 mg 21/28 ("RevLite")

Study	Dates of enrollment	Evidence
Quach et al. 2017 (RevLite)	2007 to not reported	Phase 2

Targeted therapy

• Lenalidomide (Revlimid) 15 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 to 4, 9 to 12, 17 to 20
  • Cycle 5 onwards: 20 mg PO once per day on days 1 to 4

28-day cycles

Regimen variant #4, Len @ 30 mg 21/28

Historic variant

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2006	2002-2003	Randomized Phase 2 (E-switch-ic)	Rd; twice-daily Lenalidomide	Did not meet primary endpoint of ORR

Note: This regimen variant is essentially of historical interest.

Prior treatment criteria

• Relapse after prior chemotherapy

Preceding treatment

• Lenalidomide x 2

Targeted therapy

• Lenalidomide (Revlimid) 30 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, 15 to 18

28-day cycles

References

1. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
2. MM-010: Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00424047
   1. Pooled update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article PubMed
3. MM-009: Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, Siegel D, Borrello I, Rajkumar SV, Chanan-Khan AA, Lonial S, Yu Z, Patin J, Olesnyckyj M, Zeldis JB, Knight RD; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007 Nov 22;357(21):2133-42. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00056160
   1. Pooled update: Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009 Nov;23(11):2147-52. Epub 2009 Jul 23. link to original article PubMed
4. ASPIRE: Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01080391
   1. Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article link to PMC article PubMed
   2. HRQoL analysis: Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. link to original article link to PMC article PubMed
   3. Update: Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. link to original article PubMed
5. ELOQUENT-2: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. Epub 2015 Jun 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01239797
   1. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. link to original article link to PMC article PubMed
   2. Update: Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, Signorovitch JE, Makenbaeva D, Mekan S, Sy O, Weisel K, Richardson PG. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018 Oct 15;124(20):4032-4043. Epub 2018 Sep 11. link to original article PubMed
   3. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Weisel K, San-Miguel J, Shpilberg O, Grosicki S, Špička I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Matsumoto M, Wu KL, Anderson KC, Jou YM, Ganetsky A, Singhal AK, Richardson PG. Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study. Blood Cancer J. 2020 Sep 4;10(9):91. link to original article link to PMC article PubMed
6. TOURMALINE-MM1: Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01564537
   1. Subgroup analysis: Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. Epub 2017 Oct 20. link to original article PubMed
   2. Update: Richardson PG, Kumar SK, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Gimsing P, Garderet L, Touzeau C, Buadi FK, Laubach JP, Cavo M, Darif M, Labotka R, Berg D, Moreau P. Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. J Clin Oncol. 2021 Aug 1;39(22):2430-2442. Epub 2021 Jun 11. link to original article PubMed
7. POLLUX: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol dosing details in manuscript have been reviewed by our editors PubMed NCT02076009
   1. Update: Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, Leiba M, Morton J, Ho PJ, Kim K, Takezako N, Moreau P, Kaufman JL, Sutherland HJ, Lalancette M, Magen H, Iida S, Kim JS, Prince HM, Cochrane T, Oriol A, Bahlis NJ, Chari A, O' Rourke L, Wu K, Schecter JM, Casneuf T, Chiu C, Soong D, Sasser AK, Khokhar NZ, Avet-Loiseau H, Usmani SZ. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018 Dec;103(12):2088-96. Epub 2018 Sep 20. link to original article link to PMC article PubMed
   2. Update: Bahlis NJ, Dimopoulos MA, White DJ, Benboubker L, Cook G, Leiba M, Ho PJ, Kim K, Takezako N, Moreau P, Kaufman JL, Krevvata M, Chiu C, Qin X, Okonkwo L, Trivedi S, Ukropec J, Qi M, San-Miguel J. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020 Jul;34(7):1875-1884. Epub 2020 Jan 30. link to original article link to PMC article PubMed
   3. Update: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Ahmadi T, Qin X, Garvin Mayo W, Gai X, Carey J, Carson R, Moreau P. Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2023 Mar 10;41(8):1590-1599. Epub 2023 Jan 4. link to original article link to PMC article PubMed
8. RevLite: Quach H, Fernyhough L, Henderson R, Corbett G, Baker B, Browett P, Blacklock H, Forsyth C, Underhill C, Cannell P, Trotman J, Neylon A, Harrison S, Link E, Swern A, Cowan L, Dimopoulos MA, Miles Prince H. Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study. Br J Haematol. 2017 May;177(3):441-448. Epub 2017 Feb 15. link to original articledosing details in manuscript have been reviewed by our editors PubMed NCT00482261
9. TOURMALINE-MM1 China Continuation: Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed NCT01564537
10. ReLApsE: Goldschmidt H, Baertsch MA, Schlenzka J, Becker N, Habermehl C, Hielscher T, Raab MS, Hillengass J, Sauer S, Müller-Tidow C, Luntz S, Jauch A, Hose D, Seckinger A, Brossart P, Goerner M, Klein S, Schmidt-Hieber M, Reimer P, Graeven U, Fenk R, Haenel M, Martin H, Lindemann HW, Scheid C, Nogai A, Salwender H, Noppeney R, Besemer B, Weisel K; German Myeloma Multicenter Group (GMMG). Salvage autologous transplant and lenalidomide maintenance vs lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE. Leukemia. 2021 Apr;35(4):1134-1144. Epub 2020 Jul 21. link to original article dosing details in abstract have been reviewed by our editors PubMed ISRCTN16345835

Melphalan flufenamide & Dexamethasone

Regimen

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

Note: HORIZON should not be confused with the trial by the same name in breast cancer.

Peptide-drug conjugate therapy

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

Glucocorticoid therapy

• Dexamethasone (Decadron) 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 cycles

References

1. HORIZON_RRMM: Richardson PG, Oriol A, Larocca A, Bladé J, Cavo M, Rodriguez-Otero P, Leleu X, Nadeem O, Hiemenz JW, Hassoun H, Touzeau C, Alegre A, Paner A, Maisel C, Mazumder A, Raptis A, Moreb JS, Anderson KC, Laubach JP, Thuresson S, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Mateos MV; HORIZON (OP-106) Investigators. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. J Clin Oncol. 2021 Mar 1;39(7):757-767. Epub 2020 Dec 9. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT02963493
2. OCEAN: Schjesvold FH, Dimopoulos MA, Delimpasi S, Robak P, Coriu D, Legiec W, Pour L, Špička I, Masszi T, Doronin V, Minarik J, Salogub G, Alekseeva Y, Lazzaro A, Maisnar V, Mikala G, Rosiñol L, Liberati AM, Symeonidis A, Moody V, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Hájek R, Mateos MV, Richardson PG, Sonneveld P; OCEAN (OP-103) Investigators. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study. Lancet Haematol. 2022 Feb;9(2):e98-e110. Epub 2022 Jan 12. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03151811
   1. HRQoL analysis: Schjesvold FH, Ludwig H, Delimpasi S, Robak P, Coriu D, Tomczak W, Pour L, Spicka I, Dimopoulos MA, Masszi T, Chernova NG, Sandberg A, Thuresson M, Norin S, Bakker NA, Mateos MV, Richardson PG, Sonneveld P. Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: analyses from the phase III OCEAN study. Haematologica. 2024 Jul 1;109(7):2331-2336. link to original article link to PMC article PubMed

Pomalidomide & Dexamethasone (Pd)

Pd: Pomalidomide & low-dose dexamethasone
PomDex: Pomalidomide & Dexamethasone
Pom + LoDEX: Pomalidomide & Low-dose Dexamethasone

Regimen variant #1, 4 mg 21/28

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leleu et al. 2013 (IFM 2009-02)	2009-2010	Randomized Phase 2 (E-de-esc)	Pd; 28/28	Did not meet primary endpoint of ORR
Richardson et al. 2014 (CC-4047-MM-002)	2009 to not reported	Randomized Phase 2 (E-RT-esc)	Pomalidomide	Superior PFS (primary endpoint) Median PFS: 4.2 vs 2.7 mo (HR 0.68, 95% CI 0.51-0.90)
San Miguel et al. 2013 (NIMBUS)	2011-03-18 to 2012-08-30	Phase 3 (E-RT-esc)	Dexamethasone	Superior PFS (primary endpoint) Median PFS: 4 vs 1.9 mo (HR 0.48, 95% CI 0.39-0.60) Superior OS1 (secondary endpoint) Median OS: 13.1 vs 8.1 mo (HR 0.72)
Baz et al. 2016 (PO-MM-PI-0039)	2011-2014	Randomized Phase 1/2 (C)	PomCyDex	Seems to have inferior ORR
Leleu et al. 2015 (IFM 2010-02)	2012-2013	Phase 2
Dimopoulos et al. 2016 (STRATUS)	2012-2014	Phase 3b
Mateos et al. 2019 (KEYNOTE-183)	2016-01-18 to 2017-06-07	Phase 3 (C)	PD & Pembrolizumab	Superior PFS2 Median PFS: 8.4 vs 5.6 mo (HR 0.65, 95% CI 0.45-0.95)
Dimopoulos et al. 2018 (ELOQUENT-3)	2016-03 to 2017-04	Randomized Phase 2 (C)	Elo-Pd	Inferior OS3
Oriol et al. 2024 (CheckMate 602)	2016-08 to 2018-08	Phase 3 (C)	1. NPd 2. NE-Pd	Did not meet primary endpoint of PFS
Attal et al. 2019 (ICARIA-MM)	2017-01-10 to 2018-02-02	Phase 3 (C)	Isa-Pd	Might have inferior OS
Dimopoulos et al. 2021 (APOLLO)	2017-2019	Phase 3 (C)	1a. Dara-Pd 1b. Dara-Pd (SC daratumumab)	Inferior PFS
Schjesvold et al. 2022 (OCEAN)	2017-2020	Phase 3 (C)	Melflufen flufenamide & Dexamethasone	Seems to have inferior PFS
Dimopoulos et al. 2023 (DREAMM-3)	2020-04-02 to 2022-04-18	Phase 3 (C)	Belantamab mafodotin	Did not meet primary endpoint of PFS

¹efficacy reported for NIMBUS is based on the 2015 update.
²KEYNOTE-183 was not designed to evaluate superiority in the control arm; nevertheless, an unplanned interim analysis found that the control arm had superior PFS.
³Reported efficacy for ELOQUENT-3 is based on the 2022 update.

Prior treatment criteria

• IFM 2009-02: At least 1 prior line of therapy
• CC-4047-MM-002 & NIMBUS: At least 2 prior lines of therapy including lenalidomide and bortezomib
• PO-MM-PI-0039: At least 2 prior lines of therapy including an immunomodulator; patients were required to be lenalidomide-refractory
• KEYNOTE-183: At least 2 prior lines of therapy not including pomalidomide
• ICARIA-MM: At least 2 prior lines of therapy including lenalidomide and a proteasome inhibitor
• APOLLO: At least 1 prior line of therapy including lenalidomide and a proteasome inhibitor
• OCEAN: 2 to 4 prior lines of therapy including lenalidomide and a proteasome inhibitor

Targeted therapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) by the following age-based criteria:
  • 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

Supportive therapy

• NIMBUS: Thromboprohpylaxis required. "Choice of thromboprophylaxis and use of myeloid and erythroid growth factors was left to the physician's discretion."
• IFM 2009-02: Thromboprophylaxis "at the physician's discretion"
• CC-4047-MM-002: Aspirin 81 to 100 mg PO once per day unless contraindicated
• PO-MM-PI-0039: Aspirin 81 mg PO once per day unless contraindicated
• STRATUS: Thromboprophylaxis with low-dose Aspirin, |LMWH, or equivalent was required
• IFM 2009-02: G-CSF allowed beginning with cycle 2 and on
• ICARIA-MM: mandatory Aspirin or |LMWH

28-day cycles

Regimen variant #2, 4 mg continuous

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lacy et al. 2011 (MC0789-2)	2009	Phase 2
Leleu et al. 2013 (IFM 2009-02)	2009-2010	Randomized Phase 2, >20 patients (E-esc)	Pd; 21/28	Did not meet primary endpoint of ORR

Note: Lacy et al. 2011 is registered under MC0789 but is described as a sequential phase 2 trial, distinct from Lacy et al. 2009.

Prior treatment criteria

• IFM 2009-02: At least 1 prior line of therapy

Targeted therapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 28

Glucocorticoid therapy

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

Supportive therapy

• MC0789-2: Aspirin 325 mg PO once per day
  • low molecular weight heparin or Warfarin (Coumadin) could be substituted at physician discretion
• IFM 2009-02: Thromboprophylaxis "at the physician's discretion"
• IFM 2009-02: G-CSF allowed beginning with cycle 2 and on

28-day cycles

Regimen variant #3, 2 mg continuous

Study	Dates of enrollment	Evidence
Lacy et al. 2009 (MC0789MM)	2007-2008	Phase 2

Targeted therapy

• Pomalidomide (Pomalyst) 2 mg PO once per day on days 1 to 28

Glucocorticoid therapy

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

Supportive therapy

• Aspirin 325 mg PO once per day
  • Low molecular weight heparin or Warfarin (Coumadin) could be substituted at physician discretion

28-day cycles

References

1. MC0789_MM: Lacy MQ, Hayman SR, Gertz MA, Dispenzieri A, Buadi F, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Kyle RA, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009 Oct 20;27(30):5008-14. Epub 2009 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00558896
   1. Update: Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ, Rajkumar SV, Buadi F. Pomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010 Nov;24(11):1934-9. Epub 2010 Sep 9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
   2. Update: Lacy MQ, Allred JB, Gertz MA, Hayman SR, Short KD, Buadi F, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D, Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Stewart AK, Laumann K, Mandrekar SJ, Reeder C, Rajkumar SV, Mikhael JR. Pomalidomide plus low-dose dexamethasone in myeloma refractory to both bortezomib and lenalidomide: comparison of 2 dosing strategies in dual-refractory disease. Blood. 2011 Sep 15;118(11):2970-5. Epub 2011 Jun 20. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
2. IFM 2009-02: Leleu X, Attal M, Arnulf B, Moreau P, Traulle C, Marit G, Mathiot C, Petillon MO, Macro M, Roussel M, Pegourie B, Kolb B, Stoppa AM, Hennache B, Bréchignac S, Meuleman N, Thielemans B, Garderet L, Royer B, Hulin C, Benboubker L, Decaux O, Escoffre-Barbe M, Michallet M, Caillot D, Fermand JP, Avet-Loiseau H, Facon T. Pomalidomide plus low dose dexamethasone is active and well tolerated in bortezomib and lenalidomide refractory multiple myeloma: IFM 2009-02. Blood. 2013 Mar 14;121(11):1968-1975. Epub 2013 Jan 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01053949
3. NIMBUS: San Miguel J, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-66. Epub 2013 Sep 3. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01311687
   1. Update: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. Epub 2015 Aug 6. link to original article link to PMC article PubMed
4. CC-4047-MM-002: Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, Chen C, Lonial S, Jakubowiak A, Bahlis N, Song K, Belch A, Raje N, Shustik C, Lentzsch S, Lacy M, Mikhael J, Matous J, Vesole D, Chen M, Zaki MH, Jacques C, Yu Z, Anderson K. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 Mar 20;123(12):1826-32. Epub 2014 Jan 13. Erratum in: Blood. 2014 May 15;123(20):3208-9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00833833
5. IFM 2010-02: Leleu X, Karlin L, Macro M, Hulin C, Garderet L, Roussel M, Arnulf B, Pegourie B, Kolb B, Stoppa AM, Brechiniac S, Marit G, Thielemans B, Onraed B, Mathiot C, Banos A, Lacotte L, Tiab M, Dib M, Fuzibet JG, Petillon MO, Rodon P, Wetterwald M, Royer B, Legros L, Benboubker L, Decaux O, Escoffre-Barbe M, Caillot D, Fermand JP, Moreau P, Attal M, Avet-Loiseau H, Facon T; Intergroupe Francophone du Myélome. Pomalidomide plus low-dose dexamethasone in multiple myeloma with deletion 17p and/or translocation (4;14): IFM 2010-02 trial results. Blood. 2015 Feb 26;125(9):1411-7. Epub 2015 Jan 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01745640
6. PO-MM-PI-0039: Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01432600
7. STRATUS: Dimopoulos MA, Palumbo A, Corradini P, Cavo M, Delforge M, Di Raimondo F, Weisel KC, Oriol A, Hansson M, Vacca A, Blanchard MJ, Goldschmidt H, Doyen C, Kaiser M, Petrini M, Anttila P, Cafro AM, Raymakers R, San-Miguel J, de Arriba F, Knop S, Röllig C, Ocio EM, Morgan G, Miller N, Simcock M, Peluso T, Herring J, Sternas L, Zaki MH, Moreau P. Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010): a phase 3b study in refractory multiple myeloma. Blood. 2016 Jul 28;128(4):497-503. Epub 2016 May 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01712789
8. ELOQUENT-3: Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, Leleu X, LeBlanc R, Suzuki K, Raab MS, Richardson PG, Popa McKiver M, Jou YM, Shelat SG, Robbins M, Rafferty B, San-Miguel J. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018 Nov 8;379(19):1811-1822. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02654132
   1. Update: Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, Leleu X, LeBlanc R, Suzuki K, Raab MS, Richardson PG, Popa McKiver M, Jou YM, Yao D, Das P, San-Miguel J. Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial. J Clin Oncol. 2023 Jan 20;41(3):568-578. Epub 2022 Aug 12. link to original article link to PMC article PubMed
9. KEYNOTE-183: Mateos MV, Blacklock H, Schjesvold F, Oriol A, Simpson D, George A, Goldschmidt H, Larocca A, Chanan-Khan A, Sherbenou D, Avivi I, Benyamini N, Iida S, Matsumoto M, Suzuki K, Ribrag V, Usmani SZ, Jagannath S, Ocio EM, Rodriguez-Otero P, San Miguel J, Kher U, Farooqui M, Liao J, Marinello P, Lonial S; KEYNOTE-183 Investigators. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019 Sep;6(9):e459-e469. Epub 2019 Jul 18. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02576977
10. ICARIA-MM: Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Macé S, Corzo KP, Campana F, Le-Guennec S, Dubin F, Anderson KC; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019 Dec 7;394(10214):2096-2107. Epub 2019 Nov 14. Erratum in: Lancet. 2019 Dec 7;394(10214):2072. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02990338
    1. Update: Richardson PG, Perrot A, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Malinge L, Dubin F, van de Velde H, Anderson KC. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022 Mar;23(3):416-427. Epub 2022 Feb 10. link to original article PubMed
    2. Update: Richardson PG, Perrot A, Miguel JS, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang SY, Minarik J, Cavo M, Prince HM, Macé S, Zhang R, Dubin F, Morisse MC, Anderson KC. Isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis. Haematologica. 2024 Jul 1;109(7):2239-2249. link to original article link to PMC article PubMed
11. APOLLO: Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, Symeonidis A, Bila J, Oriol A, Mateos MV, Einsele H, Orfanidis I, Ahmadi T, Ukropec J, Kampfenkel T, Schecter JM, Qiu Y, Amin H, Vermeulen J, Carson R, Sonneveld P; APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jun;22(6):801-812. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03180736
    1. Update: Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, Symeonidis A, Bila J, Oriol A, Mateos MV, Einsele H, Orfanidis I, Kampfenkel T, Liu W, Wang J, Kosh M, Tran N, Carson R, Sonneveld P. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial. Lancet Haematol. 2023 Oct;10(10):e813-e824. link to original article PubMed
12. OCEAN: Schjesvold FH, Dimopoulos MA, Delimpasi S, Robak P, Coriu D, Legiec W, Pour L, Špička I, Masszi T, Doronin V, Minarik J, Salogub G, Alekseeva Y, Lazzaro A, Maisnar V, Mikala G, Rosiñol L, Liberati AM, Symeonidis A, Moody V, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Hájek R, Mateos MV, Richardson PG, Sonneveld P; OCEAN (OP-103) Investigators. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study. Lancet Haematol. 2022 Feb;9(2):e98-e110. Epub 2022 Jan 12. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03151811
    1. HRQoL analysis: Schjesvold FH, Ludwig H, Delimpasi S, Robak P, Coriu D, Tomczak W, Pour L, Spicka I, Dimopoulos MA, Masszi T, Chernova NG, Sandberg A, Thuresson M, Norin S, Bakker NA, Mateos MV, Richardson PG, Sonneveld P. Health-related quality of life in relapsed/refractory multiple myeloma treated with melflufen and dexamethasone: analyses from the phase III OCEAN study. Haematologica. 2024 Jul 1;109(7):2331-2336. link to original article link to PMC article PubMed
13. DREAMM-3: Dimopoulos MA, Hungria VTM, Radinoff A, Delimpasi S, Mikala G, Masszi T, Li J, Capra M, Maiolino A, Pappa V, Chraniuk D, Osipov I, Leleu X, Low M, Matsumoto M, Sule N, Li M, McKeown A, He W, Bright S, Currie B, Perera S, Boyle J, Roy-Ghanta S, Opalinska J, Weisel K. Efficacy and safety of single-agent belantamab mafodotin versus pomalidomide plus low-dose dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-3): a phase 3, open-label, randomised study. Lancet Haematol. 2023 Oct;10(10):e801-e812. link to original article PubMed NCT04162210
14. CheckMate 602: Oriol A, Hájek R, Spicka I, Sandhu I, Cohen YC, Gatt ME, Mariz J, Cavo M, Berdeja J, Jin K, Bar M, Das P, Motte-Mohs R, Wang Y, Perumal D, Costa LJ. Nivolumab, Pomalidomide, and Elotuzumab Combination Regimens for Treatment of Relapsed and Refractory Multiple Myeloma: Results from the Phase 3 CheckMate 602 Study. Clin Lymphoma Myeloma Leuk. 2024 Oct;24(10):703-714. Epub 2024 May 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02726581
15. CANOVA: NCT03539744

Selinexor & Dexamethasone (Sd)

Sd: Selinexor & low-dose dexamethasone

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Vogl et al. 2018 (STORM)	2015-2018	Phase 2 (RT)

Targeted therapy

• Selinexor (Xpovio) 80 mg PO once per day on days 1, 3, 8, 10, 15, 17, 22, 24

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 3, 8, 10, 15, 17, 22, 24

28-day cycles

References

1. STORM: Vogl DT, Dingli D, Cornell RF, Huff CA, Jagannath S, Bhutani D, Zonder J, Baz R, Nooka A, Richter J, Cole C, Vij R, Jakubowiak A, Abonour R, Schiller G, Parker TL, Costa LJ, Kaminetzky D, Hoffman JE, Yee AJ, Chari A, Siegel D, Fonseca R, Van Wier S, Ahmann G, Lopez I, Kauffman M, Shacham S, Saint-Martin JR, Picklesimer CD, Choe-Juliak C, Stewart AK. Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 20;36(9):859-866. Epub 2018 Jan 30. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02336815
   1. Update: Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, Moreau P, Dingli D, Cole C, Lonial S, Dimopoulos M, Stewart AK, Richter J, Vij R, Tuchman S, Raab MS, Weisel KC, Delforge M, Cornell RF, Kaminetzky D, Hoffman JE, Costa LJ, Parker TL, Levy M, Schreder M, Meuleman N, Frenzel L, Mohty M, Choquet S, Schiller G, Comenzo RL, Engelhardt M, Illmer T, Vlummens P, Doyen C, Facon T, Karlin L, Perrot A, Podar K, Kauffman MG, Shacham S, Li L, Tang S, Picklesimer C, Saint-Martin JR, Crochiere M, Chang H, Parekh S, Landesman Y, Shah J, Richardson PG, Jagannath S. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019 Aug 22;381(8):727-738. link to original article PubMed

Thalidomide & Dexamethasone (TD)

TD: Thalidomide, Dexamethasone
Thal-Dex: Thalidomide, Dexamethasone

Regimen variant #1, thalidomide 150

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Xia et al. 2023 (CPT-MM301)	2015-02-25 to 2019-07-03	Phase 3 (C)	Thal-Dex & Aponermin	Inferior OS (secondary endpoint) Inferior PFS (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Eligibility criteria

• CPT-MM301: 18 to 75 years old

Prior treatment criteria

• CPT-MM301: Two or more prior regimens and not eligible for HSCT

Targeted therapy

• Thalidomide (Thalomid) 150 mg PO once per day

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

28-day cycle for up to 18 cycles

Regimen variant #2, thalidomide 200, with lead-in

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hjorth et al. 2012 (NMSG 17/07)	2007-2010	Phase 3 (E-switch-ooc)	Bort-Dex	Did not meet primary endpoint of PFS

Note: This was an experimental arm that did not meet its primary endpoint, likely due to premature close of the study; included here because it was eventually used to establish this regimen as a standard comparator.

Prior treatment criteria

• NMSG 17/07: Failure of melphalan with no prior exposure to bortezomib or thalidomide

Targeted therapy

• Thalidomide (Thalomid) 50 mg PO once per day, increased by 50 mg every 3 weeks to a maximum of 200 mg PO once per day

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive therapy

• "Antithrombotic prophylaxis and acyclovir prophylaxis were not mandatory according to the study protocol but used routinely in an increasing proportion of participating centers during the study period."

21-day cycles until progression or best response, which would then be followed by 1 to 2 additional cycles

Regimen variant #3, thalidomide 200

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garderet et al. 2012 (MMVAR/IFM 2005-04)	2006-2010	Phase 3 (C)	VTD	Inferior TTP

Prior treatment criteria

• At least 1 autologous stem-cell transplant

Targeted therapy

• Thalidomide (Thalomid) 200 mg PO once per day

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive therapy

• Enoxaparin (Lovenox) 40 mg SC once per day for primary prophylaxis
• Warfarin (Coumadin) for secondary prophylaxis

21-day cycle for 18 cycles (1 year)

Regimen variant #4, thalidomide 400, with lead-in

Study	Dates of enrollment	Evidence
Dimopoulos et al. 2001	1999-2000	Phase 2

Targeted therapy

• Thalidomide (Thalomid) as follows:
  • Cycle 1: 200 mg PO once per day for 14 days, then 400 mg PO once per day
  • Cycle 2 onwards: 400 mg PO once per day

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycle 1: 20 mg PO once per day on days 1 to 4, 9 to 12, 17 to 20
  • Cycle 2 onwards: 20 mg PO once per day on days 1 to 4

1-month cycles

References

1. Dimopoulos MA, Zervas K, Kouvatseas G, Galani E, Grigoraki V, Kiamouris C, Vervessou E, Samantas E, Papadimitriou C, Economou O, Gika D, Panayiotidis P, Christakis I, Anagnostopoulos N. Thalidomide and dexamethasone combination for refractory multiple myeloma. Ann Oncol. 2001 Jul;12(7):991-5. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. NMSG 17/07: Hjorth M, Hjertner Ø, Knudsen LM, Gulbrandsen N, Holmberg E, Pedersen PT, Andersen NF, Andréasson B, Billström R, Carlson K, Carlsson MS, Flogegård M, Forsberg K, Gimsing P, Karlsson T, Linder O, Nahi H, Othzén A, Swedin A; Nordic Myeloma Study Group. Thalidomide and dexamethasone vs bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. Eur J Haematol. 2012 Jun;88(6):485-96. Epub 2012 Mar 30. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00602511
3. MMVAR/IFM 2005-04: Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00256776
4. CPT-MM301: Xia Z, Leng Y, Fang B, Liang Y, Li W, Fu C, Yang L, Ke X, Jiang H, Weng J, Liu L, Zhao Y, Zhang X, Huang Z, Liu A, Shi Q, Gao Y, Chen X, Pan L, Cai Z, Wang Z, Wang Y, Fan Y, Hou M, Ma Y, Hu J, Liu J, Zhou J, Zhang X, Meng H, Lu X, Li F, Ren H, Huang B, Shao Z, Zhou H, Hu Y, Yang S, Zheng X, Wei P, Pang H, Yu W, Liu Y, Gao S, Yan L, Ma Y, Jing H, Du J, Ling W, Zhang J, Sui W, Wang F, Li X, Chen W. Aponermin or placebo in combination with thalidomide and dexamethasone in the treatment of relapsed or refractory multiple myeloma (CPT-MM301): a randomised, double-blinded, placebo-controlled, phase 3 trial. BMC Cancer. 2023 Oct 14;23(1):980. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed ChiCTR-IPR-15006024

Relapsed or refractory, triplets

BBD

BBD: Bendamustine, Bortezomib, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Ludwig et al. 2013 (AFAC BBD)	2010-2012	Phase 2

Chemotherapy

• Bendamustine 70 mg/m² IV once per day on days 1 & 4

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg (route not specified) once per day on days 1, 4, 8, 11

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 4, 8, 11

28-day cycle for up to 8 cycles

References

1. AFAC BBD: Ludwig H, Kasparu H, Leitgeb C, Rauch E, Linkesch W, Zojer N, Greil R, Seebacher A, Pour L, Weißmann A, Adam Z. Bendamustine-bortezomib-dexamethasone is an active and well tolerated regimen in patients with relapsed or refractory multiple myeloma. Blood. 2014 Feb 13;123(7):985-91. Epub 2013 Nov 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed EudraCT 2008-006421-13

BID

BID: Bendamustine, Ixazomib, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Dhakal et al. 2019 (PRO00024991)	2015-2018	Phase 1/2, fewer than 20 pts in MTD cohort

Note: Dosages listed are the determined maximally tolerated doses (MTD) of this phase 1/2 trial. Note that dexamethasone is not given in week 4; this has been confirmed with the authors.

Chemotherapy

• Bendamustine 80 mg/m² IV once per day on days 1 & 2

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
  • Older than 75 years old: 20 mg PO once per day on days 1, 8, 15

Targeted therapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15

28-day cycle for up to 8 cycles

References

1. PRO00024991: Dhakal B, D'Souza A, Hamadani M, Arce-Lara C, Schroeder K, Chhabra S, Shah NN, Gauger K, Keaton T, Pasquini M, Hari P. Phase I/II trial of bendamustine, ixazomib, and dexamethasone in relapsed/refractory multiple myeloma. Blood Cancer J. 2019 Jul 29;9(8):56. link to original article link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02477215

BLD

BLD: Bendamustine, Lenalidomide, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Lentzsch et al. 2012 (UPMC 07-089)	2008-2011	Phase 1/2

Note: Dosages listed are the determined maximally tolerated doses (MTD) of this phase 1/2 trial.

Chemotherapy

• Bendamustine 75 mg/m² IV once per day on days 1 & 2

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg (no route specified) once per day on days 1, 8, 15, 22

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

Supportive therapy

• Aspirin 325 mg PO once per day
• "Gastroprotectant" (H2-blocker or PPI)

28-day cycle for up to 8 cycles

References

1. UPMC 07-089: Lentzsch S, O'Sullivan A, Kennedy RC, Abbas M, Dai L, Pregja SL, Burt S, Boyiadzis M, Roodman GD, Mapara MY, Agha M, Waas J, Shuai Y, Normolle D, Zonder JA. Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study. Blood. 2012 May 17;119(20):4608-13. Epub 2012 Mar 26. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01042704

Bortezomib & Dexamethasone (Vd) & Panobinostat

Vd & Panobinostat: Velcade (Bortezomib), low-dose dexamethasone, Panobinostat

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2013 (PANORAMA 2)	2010-2011	Phase 2
San-Miguel et al. 2014 (PANORAMA 1)	2010-2012	Phase 3 (E-RT-esc)	Vd	Superior PFS (primary endpoint) Median PFS: 12 vs 8.1 mo (HR 0.63, 95% CI 0.52-0.76)

Patients who had clinical benefit per the modified European Group for Blood and Marrow Transplantation [EBMT] criteria on day 1 of cycle 8 proceeded to cycle 9:

Prior treatment criteria

• PANORAMA 1: 1 to 3 prior lines of therapy

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² IV once per day on days 1, 4, 8, 11
  • Cycles 9 to 16: 1.3 mg/m² IV once per day on days 1 & 8
• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 9 to 16: 20 mg PO once per day on days 1, 2, 8, 9

21-day cycle for varying durations: 16 cycles (PANORAMA 1); indefinitely (PANORAMA 2)

References

1. PANORAMA 2: Richardson PG, Schlossman RL, Alsina M, Weber DM, Coutre SE, Gasparetto C, Mukhopadhyay S, Ondovik MS, Khan M, Paley CS, Lonial S. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013 Oct 3;122(14):2331-7. Epub 2013 Aug 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01083602
2. PANORAMA 1: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Corradini P, Chuncharunee S, Lee JJ, Schlossman RL, Shelekhova T, Yong K, Tan D, Numbenjapon T, Cavenagh JD, Hou J, LeBlanc R, Nahi H, Qiu L, Salwender H, Pulini S, Moreau P, Warzocha K, White D, Bladé J, Chen W, de la Rubia J, Gimsing P, Lonial S, Kaufman JL, Ocio EM, Veskovski L, Sohn SK, Wang MC, Lee JH, Einsele H, Sopala M, Corrado C, Bengoudifa BR, Binlich F, Richardson PG. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1195-206. Epub 2014 Sep 18. Erratum in: Lancet Oncol. 2015 Jan;16(1):e6. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01023308
   1. Subgroup analysis: Richardson PG, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Guenther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Corrado C, Binlich F, San-Miguel JF. Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment. Blood. 2016 Feb 11;127(6):713-21. Epub 2015 Dec 2. link to original article link to PMC article PubMed
   2. Update: San-Miguel JF, Hungria VT, Yoon SS, Beksac M, Dimopoulos MA, Elghandour A, Jedrzejczak WW, Günther A, Nakorn TN, Siritanaratkul N, Schlossman RL, Hou J, Moreau P, Lonial S, Lee JH, Einsele H, Sopala M, Bengoudifa BR, Binlich F, Richardson PG. Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial. Lancet Haematol. 2016 Nov;3(11):e506-e515. Epub 2016 Oct 14. link to original article PubMed

BPd

BPd: Belantamab mafodotin, Pomalidomide, low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2024 (DREAMM-8)	2020-10 to 2022-12	Phase 3 (E-switch-ooc)	PVd	Superior PFS (primary endpoint) PFS12: 71% vs 51% (HR 0.52, 95% CI 0.37-0.73)

Prior treatment criteria

• At least 1 prior line of therapy

Antibody-drug conjugate therapy

• Belantamab mafodotin (Blenrep) as follows:
  • Cycle 1: 2.5 mg/kg IV once on day 1
  • Cycle 2 onwards: 1.9 mg/kg IV once on day 1

Targeted therapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) by the following criteria:
  • 75 years old and younger without comorbidities: 40 mg PO once per day on days 1, 8, 15, 22
  • Older than 75 years old or with comorbidities: 20 mg PO once per day on days 1, 8, 15, 22

28-day cycles

References

1. DREAMM-8: Dimopoulos MA, Beksac M, Pour L, Delimpasi S, Vorobyev V, Quach H, Spicka I, Radocha J, Robak P, Kim K, Cavo M, Suzuki K, Morris K, Pompilus F, Phillips-Jones A, Zhou XL, Fulci G, Sule N, Kremer BE, Opalinska J, Mateos MV, Trudel S; DREAMM-8 Investigators. Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma. N Engl J Med. 2024 Aug 1;391(5):408-421. Epub 2024 Jun 2. link to original article dosing details in protocol have been reviewed by our editors PubMed NCT04484623

BTD

BTD: Bendamustine, Thalidomide, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Schey et al. 2015 (MUKone)	2011-2012	Randomized Phase 2 (E-de-esc)	BTD; higher-dose benadmustine	Not reported1

¹While this study was randomized, it was "not powered to directly compare the two arms for statistically significant superiority."
Note: This study involved two doses of bendamustine but the higher dose was too toxic, leading to premature closure. Note that dosage listed is the lower dose. Also, the abstracts says that thalidomide is given days 1 to 21 but the body of the paper says days 1 to 28.

Chemotherapy

• Bendamustine 60 mg/m² IV once per day on days 1 & 8

Glucocorticoid therapy

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

Targeted therapy

• Thalidomide (Thalomid) 100 mg PO once per day on days 1 to 21 (see note)

Supportive therapy

• Thromboprophylaxis (not specified)
• Anti-infective prophylaxis (not specified)

28-day cycle for 6 to 9 cycles (2 cycles past best response)

References

1. MUKone: Schey S, Brown SR, Tillotson AL, Yong K, Williams C, Davies F, Morgan G, Cavenagh J, Cook G, Cook M, Orti G, Morris C, Sherratt D, Flanagan L, Gregory W, Cavet J; Myeloma UK Early Phase Clinical Trial Network. Bendamustine, thalidomide and dexamethasone combination therapy for relapsed/refractory myeloma patients: results of the MUKone randomized dose selection trial. Br J Haematol. 2015 Aug;170(3):336-48. Epub 2015 Apr 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN90889843

BVd

BVd: Belantamab mafodotin, Velcade (Bortezomib), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Hungria et al. 2024 (DREAMM-7)	2020-05-07 to 2021-06-28	Phase 3 (E-switch-ooc)	Dara-Vd	Superior PFS (primary endpoint) PFS12: 71% vs 51% (HR 0.52, 95% CI 0.37-0.73)

Prior treatment criteria

• At least 1 prior line of therapy

Antibody-drug conjugate therapy

• Belantamab mafodotin (Blenrep) 2.5 mg/kg IV once on day 1

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² SC once per day on days 1, 4, 8, 11

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 20 mg IV or PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycles

References

1. DREAMM-7: Hungria V, Robak P, Hus M, Zherebtsova V, Ward C, Ho PJ, Ribas de Almeida AC, Hajek R, Kim K, Grosicki S, Sia H, Bryant A, Pitombeira de Lacerda M, Aparecida Martinez G, Sureda Balarí AM, Sandhu I, Cerchione C, Ganly P, Dimopoulos M, Fu C, Garg M, Abdallah AO, Oriol A, Gatt ME, Cavo M, Rifkin R, Fujisaki T, Mielnik M, Pirooz N, McKeown A, McNamara S, Zhou X, Nichols M, Lewis E, Rogers R, Baig H, Eccersley L, Roy-Ghanta S, Opalinska J, Mateos MV; DREAMM-7 Investigators. Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Aug 1;391(5):393-407. link to original article dosing details in protocol have been reviewed by our editors PubMed NCT04246047

CPR

CPR: Cyclophosphamide, Prednisone, Revlimid (Lenalidomide)
REP: Revlimid (Lenalidomide), Endoxan (Cyclophosphamide), Prednisone

Regimen variant #1, "REP"

Study	Dates of enrollment	Evidence
Nijhof et al. 2016 (REPEAT)	2011-2014	Phase 1/2

Note: Details are for the MTD/phase 2 portion of the published phase 1/2 trial.

Targeted therapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day on days 1 to 28

Glucocorticoid therapy

• Prednisone (Sterapred) 20 mg PO once per day on days 1 to 28

28-day cycles

Regimen variant #2, "CPR"

Study	Dates of enrollment	Evidence
Reece et al. 2014	2007-2009	Phase 1/2

Note: Details are for the phase 2 portion of the published phase 1/2 trial.

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² PO on days 1, 8, 15

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once every other day on days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27

Targeted therapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles

References

1. Reece DE, Masih-Khan E, Atenafu EG, Jimenez-Zepeda VH, Anglin P, Chen C, Kukreti V, Mikhael JR, Trudel S. Phase I-II trial of oral cyclophosphamide, prednisone and lenalidomide for the treatment of patients with relapsed and refractory multiple myeloma. Br J Haematol. 2015 Jan;168(1):46-54. Epub 2014 Aug 22. link to original article dosing details in abstract have been reviewed by our editors PubMed
2. REPEAT: Nijhof IS, Franssen LE, Levin MD, Bos GM, Broijl A, Klein SK, Koene HR, Bloem AC, Beeker A, Faber LM, van der Spek E, Ypma PF, Raymakers R, van Spronsen DJ, Westerweel PE, Oostvogels R, van Velzen J, van Kessel B, Mutis T, Sonneveld P, Zweegman S, Lokhorst HM, van de Donk NW. Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma. Blood. 2016 Nov;128(19), 2297-2306. Epub 2016 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01352338

CRd

CRd: Cyclophosphamide, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Schey et al. 2010	Not reported	Phase 1/2

Note: This is the MTD of this phase 1/2 trial.

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg PO once per day on days 1 & 8

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1 to 4, 8 to 11

Targeted therapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Supportive therapy

• Aspirin 75 mg PO once per day

28-day cycles

References

1. Schey SA, Morgan GJ, Ramasamy K, Hazel B, Ladon D, Corderoy S, Jenner M, Phekoo K, Boyd K, Davies FE. The addition of cyclophosphamide to lenalidomide and dexamethasone in multiply relapsed/refractory myeloma patients; a phase I/II study. Br J Haematol. 2010 Aug;150(3):326-33. Epub 2010 Jun 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed

CTD

CTD: Cyclophosphamide, Thalidomide, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Dimopoulos et al. 2004	Not reported in abstract	Phase 2

Chemotherapy

• Cyclophosphamide (Cytoxan) 150 mg/m² PO every 12 hours on days 1 to 5, taken before meals

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 3: 20 mg PO once per day on days 1 to 5, 14 to 18, taken every morning after breakfast
  • Cycle 4 onwards: 20 mg PO once per day on days 1 to 5, taken every morning after breakfast

Targeted therapy

• Thalidomide (Thalomid) as follows:
  • Cycles 1 to 3: 400 mg PO once per day on days 1 to 5, 14 to 18, taken in the evening
  • Cycle 4 onwards: 400 mg PO once per day on days 1 to 5, taken in the evening

28-day cycles

References

1. Dimopoulos MA, Hamilos G, Zomas A, Gika D, Efstathiou E, Grigoraki V, Poziopoulos C, Xilouri I, Zorzou MP, Anagnostopoulos N, Anagnostopoulos A. Pulsed cyclophosphamide, thalidomide and dexamethasone: an oral regimen for previously treated patients with multiple myeloma. Hematol J. 2004;5(2):112-7. link to original article PubMed

Dara-Kd

Dara-Kd: Daratumumab, Kyprolis (Carfilzomib), low-dose dexamethasone
D-Kd: Daratumumab, Kyprolis (Carfilzomib), low-dose dexamethasone
KdD: Kyprolis (Carfilzomib), low-dose dexamethasone, Daratumumab

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2020 (CANDOR)	2017-06-13 to 2018-06-25	Phase 3 (E-RT-esc)	Kd	Superior PFS1 (primary endpoint) Median PFS: 28.6 vs 15.2 mo (HR 0.59, 95% CI 0.45-0.78)

¹Reported efficacy is based on the 2021 update.
Note: this dosing if for patients 75 or younger; the steroid dosing is fairly complex; refer to page 45 of the protocol for additional details.

Prior treatment criteria

• 1 to 3 prior lines of therapy

Targeted therapy

• Daratumumab (Darzalex) as follows:
  • Cycle 1: 8 mg/kg IV once per day on days 1 & 2, then 16 mg/kg IV once per day on days 8, 15, 22
  • Cycle 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
• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once per day on days 1 & 2, then 56 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 56 mg/m² IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2020 (CANDOR)	2017-06-13 to 2018-06-25	Phase 3 (E-RT-esc)	Kd	Superior PFS1 (primary endpoint) Median PFS: 28.6 vs 15.2 mo (HR 0.59, 95% CI 0.45-0.78)

¹Reported efficacy is based on the 2021 update.
Note: this dosing is for patients older than 75; the steroid dosing is fairly complex; refer to page 45 of the protocol for additional details.

Prior treatment criteria

• 1 to 3 prior lines of therapy

Targeted therapy

• Daratumumab (Darzalex) as follows:
  • Cycle 1: 8 mg/kg IV once per day on days 1 & 2, then 16 mg/kg IV once per day on days 8, 15, 22
  • Cycle 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
• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once per day on days 1 & 2, then 56 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 56 mg/m² IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycle 1: 20 mg IV or PO once per day on days 1, 2, 8, then 8 mg IV or PO once on day 9, then 20 mg IV or PO once on day 15, then 8 mg IV or PO once on day 16, then 20 mg IV or PO once on day 22
  • Cycle 2 onwards: 20 mg IV or PO once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #3

Study	Dates of enrollment	Evidence	Efficacy
Chari et al. 2019 (EQUULEUScfz)	2014 to not reported	Phase 1b (RT)	ORR: 84%

Note: this dosing is for patients 75 or younger. EQUULEUS had multiple arms; this one is denoted as cfz (carfilzomib).

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
• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once on day 1, then 70 mg/m² IV once per day on days 8 & 15
  • Cycle 2 onwards: 70 mg/m² IV once per day on days 1, 8, 15

Glucocorticoid therapy

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

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per infusion, prior to daratumumab
  • For patients receiving the 40 mg/wk dose, the remainder is given the day after the infusion
• Acetaminophen (Tylenol) once per infusion, prior to daratumumab
• Diphenhydramine (Benadryl) once per infusion, prior to daratumumab

28-day cycles

Regimen variant #4

Study	Dates of enrollment	Evidence	Efficacy
Chari et al. 2019 (EQUULEUScfz)	2014 to not reported	Phase 1b (RT)	ORR: 84%

Note: this dosing is for patients older than 75. EQUULEUS had multiple arms; this one is denoted as cfz (carfilzomib).

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
• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once on day 1, then 70 mg/m² IV once per day on days 8 & 15
  • Cycle 2 onwards: 70 mg/m² IV once per day on days 1, 8, 15

Glucocorticoid therapy

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

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV or PO once per infusion, prior to daratumumab
  • For patients receiving the 40 mg/wk dose, the remainder is given the day after the infusion
• Acetaminophen (Tylenol) once per infusion, prior to daratumumab
• Diphenhydramine (Benadryl) once per infusion, prior to daratumumab

28-day cycles

References

1. EQUULEUS_cfz: Chari A, Martinez-Lopez J, Mateos MV, Bladé J, Benboubker L, Oriol A, Arnulf B, Rodriguez-Otero P, Pineiro L, Jakubowiak A, de Boer C, Wang J, Clemens PL, Ukropec J, Schecter J, Lonial S, Moreau P. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019 Aug 1;134(5):421-431. Epub 2019 May 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01998971
   1. Update: Moreau P, Chari A, Oriol A, Martinez-Lopez J, Haenel M, Touzeau C, Ailawadhi S, Besemer B, de la Rubia Comos J, Encinas C, Mateos MV, Salwender H, Rodriguez-Otero P, Hulin C, Karlin L, Sureda Balari A, Bargay J, Benboubker L, Rosiñol L, Tarantolo S, Terebelo H, Yang S, Wang J, Nnane I, Qi M, Kosh M, Delioukina M, Goldschmidt H. Daratumumab, carfilzomib, and dexamethasone in relapsed or refractory myeloma: final analysis of PLEIADES and EQUULEUS. Blood Cancer J. 2023 Mar 7;13(1):33. link to original article link to PMC article dosing details in supplement have been reviewed by our editors PubMed
2. CANDOR: Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Yang H, Klippel Z, Zahlten-Kumeli A, Usmani SZ. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020 Jul 18;396(10245):186-197. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03158688
   1. Update: Usmani SZ, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, Weisel K, Gavriatopoulou M, Oriol A, Rabin N, Nooka A, Qi M, Beksac M, Jakubowiak A, Ding B, Zahlten-Kumeli A, Yusuf A, Dimopoulos M. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022 Jan;23(1):65-76. Epub 2021 Dec 3. link to original article PubMed
3. REMNANT: NCT04513639

Dara-Kd (SC daratumumab)

Dara-Kd: Daratumumab and hyaluronidase, Kyprolis (Carfilzomib), low-dose dexamethasone
D-Kd: Daratumumab and hyaluronidase, Kyprolis (Carfilzomib), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Moreau et al. 2023 (PLEIADES)	2018 to not reported	Phase 2 (RT)

Note: To our knowledge, Moreau et al. 2023 is the only published manuscript describing PLEIADES.

Targeted therapy

• Daratumumab and hyaluronidase (Darzalex Faspro) as follows:
  • Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22
  • Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15
  • Cycle 7 onwards: 1800 mg SC once on day 1
• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once on day 1, then 70 mg/m² IV once per day on days 8 & 15
  • Cycle 2 onwards: 70 mg/m² IV once per day on days 1, 8, 15

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 cycles

References

1. PLEIADES: Moreau P, Chari A, Oriol A, Martinez-Lopez J, Haenel M, Touzeau C, Ailawadhi S, Besemer B, de la Rubia Comos J, Encinas C, Mateos MV, Salwender H, Rodriguez-Otero P, Hulin C, Karlin L, Sureda Balari A, Bargay J, Benboubker L, Rosiñol L, Tarantolo S, Terebelo H, Yang S, Wang J, Nnane I, Qi M, Kosh M, Delioukina M, Goldschmidt H. Daratumumab, carfilzomib, and dexamethasone in relapsed or refractory myeloma: final analysis of PLEIADES and EQUULEUS. Blood Cancer J. 2023 Mar 7;13(1):33. link to original article link to PMC article dosing details in supplement have been reviewed by our editors PubMed NCT03412565

Dara-Pd

Dara-Pd: Daratumumab, Pomalidomide, low-dose dexamethasone
DPd: Daratumumab, Pomalidomide, low-dose dexamethasone

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chari et al. 2017 (EQUULEUSpom)	2014 to not reported	Phase 1b (RT)		ORR: 59% (95% CI, 49-69)
Dimopoulos et al. 2021 (APOLLO)	2017-2019	Phase 3 (E-esc)	Pd	Superior PFS (primary endpoint) Median PFS: 12.4 vs 6.9 mo (HR 0.63, 95% CI 0.47-0.85) Did not meet secondary endpoint of OS1
Rodriguez-Otero et al. 2023 (KarMMa-3)	2019-05 to 2022-04	Phase 3 (C)	Ide-cel	Inferior PFS

¹Reported efficacy for APOLLO is based on the 2023 update.
Note: EQUULEUS had multiple arms; this one is denoted as pom (pomalidomide).

Prior treatment criteria

• APOLLO: At least 1 prior line of therapy including lenalidomide and a proteasome inhibitor

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
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) by the following criteria:
  • Standard patients: 40 mg PO once per day on days 1, 8, 15, 22
  • EQUULEUS_pom, patients older than 75 years or BMI less than 18.5: 20 mg PO once per day on days 1, 8, 15, 22
  • APOLLO & KarMMa-3, patients older than 75 years: 20 mg PO once per day on days 1, 8, 15, 22

Supportive therapy

• Details are per EQUULEUS_pom:
• Dexamethasone (Decadron) 20 mg IV or PO once per infusion, prior to daratumumab
  • For patients receiving the 40 mg/wk dose, the remainder is given after the infusion on day of infusion
• Acetaminophen (Tylenol) once per infusion, prior to daratumumab
• An antihistamine once per infusion, prior to daratumumab

28-day cycles

References

1. EQUULEUS_pom: Chari A, Suvannasankha A, Fay JW, Arnulf B, Kaufman JL, Ifthikharuddin JJ, Weiss BM, Krishnan A, Lentzsch S, Comenzo R, Wang J, Nottage K, Chiu C, Khokhar NZ, Ahmadi T, Lonial S. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017 Aug 24;130(8):974-981. Epub 2017 Jun 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01998971
2. APOLLO: Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, Symeonidis A, Bila J, Oriol A, Mateos MV, Einsele H, Orfanidis I, Ahmadi T, Ukropec J, Kampfenkel T, Schecter JM, Qiu Y, Amin H, Vermeulen J, Carson R, Sonneveld P; APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jun;22(6):801-812. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03180736
   1. Update: Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, Symeonidis A, Bila J, Oriol A, Mateos MV, Einsele H, Orfanidis I, Kampfenkel T, Liu W, Wang J, Kosh M, Tran N, Carson R, Sonneveld P. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial. Lancet Haematol. 2023 Oct;10(10):e813-e824. link to original article PubMed
3. KarMMa-3: Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M, Giralt S. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023 Mar 16;388(11):1002-1014. Epub 2023 Feb 10. link to original article dosing details in supplement have been reviewed by our editors PubMed NCT03651128
   1. PRO analysis: Delforge M, Patel K, Eliason L, Dhanda D, Shi L, Guo S, Marshall TS, Arnulf B, Cavo M, Nooka A, Manier S, Callander N, Giralt S, Einsele H, Ailawadhi S, Popa McKiver M, Cook M, Rodríguez-Otero P. Health-related quality of life in patients with triple-class exposed relapsed and refractory multiple myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial. Lancet Haematol. 2024 Mar;11(3):e216-e227. link to original article PubMed
4. MAGNETISMM-5: NCT05020236

Dara-Pd (SC daratumumab)

Dara-Pd: Daratumumab and hyaluronidase, Pomalidomide, low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2021 (APOLLO)	2017-2019	Phase 3 (E-RT-esc)	Pd	Superior PFS (primary endpoint) Median PFS: 12.4 vs 6.9 mo (HR 0.63, 95% CI 0.47-0.85) Did not meet secondary endpoint of OS1
San-Miguel et al. 2023 (CARTITUDE-4)	2020-07-10 to 2021-11-17	Phase 3 (C)	Cilta-cel	Inferior PFS

¹Reported efficacy for APOLLO is based on the 2023 update.

Prior treatment criteria

• APOLLO: At least 1 prior line of therapy including lenalidomide and a proteasome inhibitor

Targeted therapy

• Daratumumab and hyaluronidase (Darzalex Faspro) as follows:
  • Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22
  • Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15
  • Cycle 7 onwards: 1800 mg SC once on day 1
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) by the following study-specific criteria:
  • APOLLO, standard patients: 40 mg PO once per day on days 1, 8, 15, 22
  • APOLLO, patients older than 75 years: 20 mg PO once per day on days 1, 8, 15, 22
  • CARTITUDE-4, choice 1: 40 mg IV or PO once per day on days 1, 8, 15, 22
  • CARTITUDE-4, choice 2: 20 mg IV or PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles

References

1. APOLLO: Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, Symeonidis A, Bila J, Oriol A, Mateos MV, Einsele H, Orfanidis I, Ahmadi T, Ukropec J, Kampfenkel T, Schecter JM, Qiu Y, Amin H, Vermeulen J, Carson R, Sonneveld P; APOLLO Trial Investigators. Daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in previously treated multiple myeloma (APOLLO): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Jun;22(6):801-812. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03180736
   1. Update: Dimopoulos MA, Terpos E, Boccadoro M, Delimpasi S, Beksac M, Katodritou E, Moreau P, Baldini L, Symeonidis A, Bila J, Oriol A, Mateos MV, Einsele H, Orfanidis I, Kampfenkel T, Liu W, Wang J, Kosh M, Tran N, Carson R, Sonneveld P. Subcutaneous daratumumab plus pomalidomide and dexamethasone versus pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (APOLLO): extended follow up of an open-label, randomised, multicentre, phase 3 trial. Lancet Haematol. 2023 Oct;10(10):e813-e824. link to original article PubMed
2. CARTITUDE-4: San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, Fernández de Larrea C, Martínez-López J, Moreau P, Touzeau C, Leleu X, Avivi I, Cavo M, Ishida T, Kim SJ, Roeloffzen W, van de Donk NWCJ, Dytfeld D, Sidana S, Costa LJ, Oriol A, Popat R, Khan AM, Cohen YC, Ho PJ, Griffin J, Lendvai N, Lonardi C, Slaughter A, Schecter JM, Jackson CC, Connors K, Li K, Zudaire E, Chen D, Gilbert J, Yeh TM, Nagle S, Florendo E, Pacaud L, Patel N, Harrison SJ, Einsele H. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med. 2023 Jul 27;389(4):335-347. Epub 2023 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT04181827
3. MajesTEC-3: NCT05083169

Dara-Rd

Dara-Rd: Daratumumab, Revlimid (Lenalidomide), low-dose dexamethasone
D-Rd: Daratumumab, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen variant #1, limited duration

Study	Dates of enrollment	Evidence
Plesner et al. 2016 (GEN503)	2012 to not reported	Phase 1/2

Targeted therapy

• Daratumumab (Darzalex) as follows:
  • Cycles 1 & 2: 16 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycles 3 to 6: 16 mg/kg IV once per day on days 1 & 15
  • Cycles 7 to 26: 16 mg/kg IV once on day 1
• 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 26 cycles (2 years)

Regimen variant #2, indefinite

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2016 (POLLUX)	2014-06-16 to 2015-07-14	Phase 3 (E-RT-esc)	Rd	Superior PFS1 (primary endpoint) Median PFS: 44.5 vs 17.5 mo (HR 0.44, 95% CI 0.35-0.55) Superior OS2 (secondary endpoint) Median OS: 67.6 vs 51.8 mo (HR 0.73, 95% CI 0.58-0.91)

¹Reported efficacy is based on the 2020 update.
²Reported efficacy is based on the 2023 update.

Prior treatment criteria

• 1 to 3 prior lines of therapy

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 60 mL/min/1.73m² or more: 25 mg PO once per day on days 1 to 21
  • CrCl 30 to 60 mL/min/1.73m²: 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 or 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

1. GEN503: Plesner T, Arkenau HT, Gimsing P, Krejcik J, Lemech C, Minnema MC, Lassen U, Laubach JP, Palumbo A, Lisby S, Basse L, Wang J, Sasser AK, Guckert ME, de Boer C, Khokhar NZ, Yeh H, Clemens PL, Ahmadi T, Lokhorst HM, Richardson PG. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood. 2016 Oct 6;128(14):1821-8. Epub 2016 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01615029
2. POLLUX: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Komarnicki M, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Lisby S, Khokhar NZ, O'Rourke L, Chiu C, Qin X, Guckert M, Ahmadi T, Moreau P; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Oct 6;375(14):1319-1331. link to original article link to original protocol dosing details in manuscript have been reviewed by our editors PubMed NCT02076009
   1. Update: Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, Leiba M, Morton J, Ho PJ, Kim K, Takezako N, Moreau P, Kaufman JL, Sutherland HJ, Lalancette M, Magen H, Iida S, Kim JS, Prince HM, Cochrane T, Oriol A, Bahlis NJ, Chari A, O' Rourke L, Wu K, Schecter JM, Casneuf T, Chiu C, Soong D, Sasser AK, Khokhar NZ, Avet-Loiseau H, Usmani SZ. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018 Dec;103(12):2088-96. Epub 2018 Sep 20. link to original article link to PMC article PubMed
   2. Update: Bahlis NJ, Dimopoulos MA, White DJ, Benboubker L, Cook G, Leiba M, Ho PJ, Kim K, Takezako N, Moreau P, Kaufman JL, Krevvata M, Chiu C, Qin X, Okonkwo L, Trivedi S, Ukropec J, Qi M, San-Miguel J. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020 Jul;34(7):1875-1884. Epub 2020 Jan 30. link to original article link to PMC article PubMed
   3. Update: Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, Rabin N, Orlowski RZ, Suzuki K, Plesner T, Yoon SS, Ben Yehuda D, Richardson PG, Goldschmidt H, Reece D, Ahmadi T, Qin X, Garvin Mayo W, Gai X, Carey J, Carson R, Moreau P. Overall Survival With Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2023 Mar 10;41(8):1590-1599. Epub 2023 Jan 4. link to original article link to PMC article PubMed
3. CONFIRM_MM: NCT03836014

Dara-Rd (SC daratumumab)

Dara-Rd: Daratumumab and hyaluronidase, Revlimid (Lenalidomide), low-dose dexamethasone
D-Rd: Daratumumab and hyaluronidase, Revlimid (Lenalidomide), low-dose dexamethasone

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:
  • Cycles 1 & 2: 1800 mg SC once per day on days 1, 8, 15, 22
  • Cycles 3 to 6: 1800 mg SC once per day on days 1 & 15
  • Cycle 7 onwards: 1800 mg SC once on day 1
• 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 cycles

References

1. 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 PubMed NCT03412565

Dara-Vd

Dara-Vd: Daratumumab, Velcade (Bortezomib), low-dose dexamethasone
D-Vd: Daratumumab, Velcade (Bortezomib), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Palumbo et al. 2016 (CASTOR)	2014-09-04 to 2015-09-24	Phase 3 (E-RT-esc)	Vd	Superior PFS1 (primary endpoint) Median PFS: 16.7 vs 7.1 mo (HR 0.31, 95% CI 0.25-0.40) Superior OS2 (secondary endpoint) Median OS: 49.6 vs 38.5 mo (HR 0.74, 95% CI 0.59-0.92)
Lu et al. 2021 (LEPUS)	2017-2019	Phase 3 (E-esc)	Vd	Superior PFS (primary endpoint) Median PFS: NYR vs 6.3 mo (HR 0.28, 95% CI 0.17-0.47)
Rodriguez-Otero et al. 2023 (KarMMa-3)	2019-05 to 2022-04	Phase 3 (C)	Ide-cel	Inferior PFS
Hungria et al. 2024 (DREAMM-7)	2020-05-07 to 2021-06-28	Phase 3 (C)	BVd	Inferior PFS

¹Reported efficacy for the primary endpoint of CASTOR (PFS) is based on the 2019 update.
²Reported efficacy for the secondary endpoint of CASTOR (OS) is based on the 2022 update.
Note: KarMMa-3 only allowed the oral route for dexamethasone.

Prior treatment criteria

• CASTOR, DREAMM-7, LEPUS: At least 1 prior line of therapy

Targeted therapy

• Daratumumab (Darzalex) as follows:
  • Cycles 1 to 3: 16 mg/kg IV once per day on days 1, 8, 15
  • Cycle 4 onwards: 16 mg/kg IV once on day 1
• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² SC once per day on days 1, 4, 8, 11

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 20 mg IV or PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12

21-day cycle for 8 cycles, then 28-day cycles

Dose and schedule modifications

• Dexamethasone (Decadron) can be dose-reduced to 20 mg IV or PO once per day on days 1, 8, 15 for patients greater than 75 years, with BMI less than 18.5, or with previous side effects

References

1. CASTOR: Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Qi M, Schecter J, Amin H, Qin X, Deraedt W, Ahmadi T, Spencer A, Sonneveld P; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Aug 25;375(8):754-66. link to original article link to supplementary appendix dosing details in manuscript have been reviewed by our editors PubMed NCT02136134
   1. Update: Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, Masszi T, Lauri B, Levin MD, Bosi A, Hungria V, Cavo M, Lee JJ, Nooka AK, Quach H, Lee C, Barreto W, Corradini P, Min CK, Scott EC, Chanan-Khan AA, Horvath N, Capra M, Beksac M, Ovilla R, Jo JC, Shin HJ, Sonneveld P, Soong D, Casneuf T, Chiu C, Amin H, Qi M, Thiyagarajah P, Sasser AK, Schecter JM, Mateos MV. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018 Dec;103(12):2079-87. Epub 2018 Sep 20. link to original article link to PMC article PubMed
   2. Update: Mateos MV, Sonneveld P, Hungria V, Nooka AK, Estell JA, Barreto W, Corradini P, Min CK, Medvedova E, Weisel K, Chiu C, Schecter JM, Amin H, Qin X, Ukropec J, Kobos R, Spencer A. Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Patients With Previously Treated Multiple Myeloma: Three-year Follow-up of CASTOR. Clin Lymphoma Myeloma Leuk. 2020 Aug;20(8):509-518. Epub 2019 Oct 9. link to original article PubMed
   3. Update: Sonneveld P, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, Spicka I, Hungria V, Munder M, Mateos MV, Mark TM, Levin MD, Ahmadi T, Qin X, Garvin Mayo W, Gai X, Carey J, Carson R, Spencer A. Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial. J Clin Oncol. 2023 Mar 10;41(8):1600-1609. Epub 2022 Nov 22. link to original article link to PMC article PubMed
2. LEPUS: Lu J, Fu W, Li W, Hu J, An G, Wang Y, Fu C, Chen L, Jin J, Cen X, Ge Z, Cai Z, Niu T, Qi M, Sun S, Gai X, Liu W, Liu W, Yang X, Huang X. Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Chinese Patients with Relapsed or Refractory Multiple Myeloma: Phase 3 LEPUS (MMY3009) Study. Clin Lymphoma Myeloma Leuk. 2021 Sep;21(9):e699-e709. Epub 2021 Apr 24. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT03234972
3. KarMMa-3: Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M, Giralt S. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023 Mar 16;388(11):1002-1014. Epub 2023 Feb 10. link to original article dosing details in supplement have been reviewed by our editors PubMed NCT03651128
   1. PRO analysis: Delforge M, Patel K, Eliason L, Dhanda D, Shi L, Guo S, Marshall TS, Arnulf B, Cavo M, Nooka A, Manier S, Callander N, Giralt S, Einsele H, Ailawadhi S, Popa McKiver M, Cook M, Rodríguez-Otero P. Health-related quality of life in patients with triple-class exposed relapsed and refractory multiple myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial. Lancet Haematol. 2024 Mar;11(3):e216-e227. link to original article PubMed
4. DREAMM-7: Hungria V, Robak P, Hus M, Zherebtsova V, Ward C, Ho PJ, Ribas de Almeida AC, Hajek R, Kim K, Grosicki S, Sia H, Bryant A, Pitombeira de Lacerda M, Aparecida Martinez G, Sureda Balarí AM, Sandhu I, Cerchione C, Ganly P, Dimopoulos M, Fu C, Garg M, Abdallah AO, Oriol A, Gatt ME, Cavo M, Rifkin R, Fujisaki T, Mielnik M, Pirooz N, McKeown A, McNamara S, Zhou X, Nichols M, Lewis E, Rogers R, Baig H, Eccersley L, Roy-Ghanta S, Opalinska J, Mateos MV; DREAMM-7 Investigators. Belantamab Mafodotin, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2024 Aug 1;391(5):393-407. link to original article dosing details in protocol have been reviewed by our editors PubMed NCT04246047
5. EXCALIBER-RRMM: NCT04975997

Dara-Vd (SC daratumumab)

Dara-Vd: Daratumumab and hyaluronidase, Velcade (Bortezomib), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Awaiting publication (MajesTEC-3)	2021-ongoing	Phase 3 (C)	Tec-Dara	TBD if different primary endpoint of PFS

Targeted therapy

• Daratumumab and hyaluronidase (Darzalex Faspro)
• Bortezomib (Velcade)

Glucocorticoid therapy

• Dexamethasone (Decadron)

References

1. MajesTEC-3: NCT05083169

Elo-Pd

Elo-Pd: Elotuzumab, Pomalidomide, low-dose dexamethasone
EPd: Elotuzumab, Pomalidomide, low-dose dexamethasone

Regimen variant #1, lower-dose dexamethasone

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2018 (ELOQUENT-3)	2016-03 to 2017-04	Randomized Phase 2 (E-RT-esc)	Pd	Superior OS1 (secondary endpoint) Median OS: 29.8 vs 17.4 mo (HR 0.59, 95% CI 0.37-0.93) Superior PFS (primary endpoint) Median PFS: 10.3 vs 4.7 mo (HR 0.54, 95% CI 0.34-0.86)
Rodriguez-Otero et al. 2023 (KarMMa-3)	2019-05 to 2022-04	Phase 3 (C)	Ide-cel	Inferior PFS

¹Reported efficacy for ELOQUENT-3 is based on the 2022 update.
Note: this variant was intended for patients older than 75 years.

Prior treatment criteria

• 2 or more prior lines of therapy, including lenalidomide and a proteasome inhibitor

Targeted therapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycle 3 onwards: 20 mg/kg IV once on day 1
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Weeks without elotuzumab: 20 mg PO once per week
  • Weeks with elotuzumab: 8 mg PO once per infusion, prior to elotuzumab, then 8 mg IV once per infusion, on days when elotuzumab is administered
    • According to the elotuzumab package insert, the first dose should be given between 3 and 24 hours before elotuzumab; the second dose should be given 45 to 90 minutes before elotuzumab.

Supportive therapy

• Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) or its equivalent once per infusion, 45 to 90 minutes prior to elotuzumab
• Ranitidine (Zantac) 50 mg (route not specified) or its equivalent once per infusion, 45 to 90 minutes prior to elotuzumab
• Acetaminophen (Tylenol) 650 to 1000 mg (route not specified) once per infusion, 45 to 90 minutes prior to elotuzumab
• "Thromboembolic prophylaxis was required "according to institutional guidelines or at the discretion of the investigator."

28-day cycles

Regimen variant #2, standard-dose dexamethasone

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2018 (ELOQUENT-3)	2016-03 to 2017-04	Randomized Phase 2 (E-esc)	Pd	Superior OS1 (secondary endpoint) Median OS: 29.8 vs 17.4 mo (HR 0.59, 95% CI 0.37-0.93) Superior PFS (primary endpoint) Median PFS: 10.3 vs 4.7 mo (HR 0.54, 95% CI 0.34-0.86)
Rodriguez-Otero et al. 2023 (KarMMa-3)	2019-05 to 2022-04	Phase 3 (C)	Ide-cel	Inferior PFS

¹Reported efficacy for ELOQUENT-3 is based on the 2022 update.
Note: this variant was intended for patients up to 75 years.

Prior treatment criteria

• 2 or more prior lines of therapy, including lenalidomide and a proteasome inhibitor

Targeted therapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycle 3 onwards: 20 mg/kg IV once on day 1
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Weeks without elotuzumab: 40 mg PO once per week
  • Weeks with elotuzumab: 28 mg PO once per infusion, prior to elotuzumab, then 8 mg IV once per infusion, on days when elotuzumab is administered
    • According to the elotuzumab package insert, the first dose should be given between 3 and 24 hours before elotuzumab; the second dose should be given 45 to 90 minutes before elotuzumab.

Supportive therapy

• Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) or its equivalent once per infusion, 45 to 90 minutes prior to elotuzumab
• Ranitidine (Zantac) 50 mg (route not specified) or its equivalent once per infusion, 45 to 90 minutes prior to elotuzumab
• Acetaminophen (Tylenol) 650 to 1000 mg (route not specified) once per infusion, 45 to 90 minutes prior to elotuzumab
• "Thromboembolic prophylaxis was required "according to institutional guidelines or at the discretion of the investigator."

28-day cycles

References

1. ELOQUENT-3: Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, Leleu X, LeBlanc R, Suzuki K, Raab MS, Richardson PG, Popa McKiver M, Jou YM, Shelat SG, Robbins M, Rafferty B, San-Miguel J. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018 Nov 8;379(19):1811-1822. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02654132
   1. Update: Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, Leleu X, LeBlanc R, Suzuki K, Raab MS, Richardson PG, Popa McKiver M, Jou YM, Yao D, Das P, San-Miguel J. Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial. J Clin Oncol. 2023 Jan 20;41(3):568-578. Epub 2022 Aug 12. link to original article link to PMC article PubMed
2. KarMMa-3: Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M, Giralt S. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023 Mar 16;388(11):1002-1014. Epub 2023 Feb 10. link to original article dosing details in supplement have been reviewed by our editors PubMed NCT03651128
   1. PRO analysis: Delforge M, Patel K, Eliason L, Dhanda D, Shi L, Guo S, Marshall TS, Arnulf B, Cavo M, Nooka A, Manier S, Callander N, Giralt S, Einsele H, Ailawadhi S, Popa McKiver M, Cook M, Rodríguez-Otero P. Health-related quality of life in patients with triple-class exposed relapsed and refractory multiple myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial. Lancet Haematol. 2024 Mar;11(3):e216-e227. link to original article PubMed
3. EMN29: NCT05028348

Elo-Rd

Elo-Rd: Elotuzumab, Revlimid (Lenalidomide), low-dose dexamethasone
ELd: Elotuzumab, Lenalidomide, low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lonial et al. 2012 (1703 Study)	2008 to not reported	Phase 1b/2
Lonial et al. 2015 (ELOQUENT-2)	2011-06 to 2012-11	Phase 3 (E-RT-esc)	Rd	Seems to have superior OS1 (secondary endpoint) Median OS: 48.3 vs 39.6 mo (HR 0.82, 95.4% CI 0.68-1.00) Superior PFS (primary endpoint) Median PFS: 19.4 vs 14.9 mo (HR 0.70, 95% CI 0.57-0.85)

¹Reported OS efficacy for ELOQUENT-2 is based on the 2020 final update.

Prior treatment criteria

• ELOQUENT-2: 1 to 3 prior lines of therapy

Targeted therapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycle 3 onwards: 10 mg/kg IV once per day on days 1 & 15
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Weeks without elotuzumab: 40 mg PO once per week
  • Weeks with elotuzumab: 28 mg PO once per infusion, prior to elotuzumab, then 8 mg IV once per infusion, after elotuzumab is administered
    • According to the elotuzumab package insert, the 28 mg PO dose should be given between 3 and 24 hours before elotuzumab; the 8 mg IV dose should be given 45 to 90 minutes before elotuzumab.

Supportive therapy

• Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) or its equivalent once per infusion, 30 to 90 minutes prior to elotuzumab
• Ranitidine (Zantac) 50 mg (route not specified) or its equivalent one per infusion, 30 to 90 minutes prior to elotuzumab
• Acetaminophen (Tylenol) 650 to 1000 mg (route not specified) or its equivalent once per infusion, 30 to 90 minutes prior to elotuzumab
• "Thromboembolic prophylaxis (e.g., aspirin, low-molecular-weight heparin, or vitamin K antagonists) was administered according to institutional guidelines or at the discretion of the investigator."

28-day cycles

References

1. 1703 Study: Lonial S, Vij R, Harousseau JL, Facon T, Moreau P, Mazumder A, Kaufman JL, Leleu X, Tsao LC, Westland C, Singhal AK, Jagannath S. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J Clin Oncol. 2012 Jun 1;30(16):1953-9. Epub 2012 Apr 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00742560
   1. Update: Richardson PG, Jagannath S, Moreau P, Jakubowiak AJ, Raab MS, Facon T, Vij R, White D, Reece DE, Benboubker L, Zonder J, Tsao LC, Anderson KC, Bleickardt E, Singhal AK, Lonial S; 1703 study investigators. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2015 Dec;2(12):e516-27. Epub 2015 Nov 16. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed
2. ELOQUENT-2: Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, Walter-Croneck A, Moreau P, Mateos MV, Magen H, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Wu KL, Singhal A, San-Miguel J, Matsumoto M, Katz J, Bleickardt E, Poulart V, Anderson KC, Richardson P; ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015 Aug 13;373(7):621-31. Epub 2015 Jun 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01239797
   1. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Palumbo A, San-Miguel J, Shpilberg O, Anderson K, Grosicki S, Spicka I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Bleickardt E, Poulart V, Sheng J, Sy O, Katz J, Singhal A, Richardson P. Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth. Br J Haematol. 2017 Sep;178(6):896-905. Epub 2017 Jul 5. link to original article link to PMC article PubMed
   2. Update: Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, Signorovitch JE, Makenbaeva D, Mekan S, Sy O, Weisel K, Richardson PG. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018 Oct 15;124(20):4032-4043. Epub 2018 Sep 11. link to original article PubMed
   3. Update: Dimopoulos MA, Lonial S, White D, Moreau P, Weisel K, San-Miguel J, Shpilberg O, Grosicki S, Špička I, Walter-Croneck A, Magen H, Mateos MV, Belch A, Reece D, Beksac M, Spencer A, Oakervee H, Orlowski RZ, Taniwaki M, Röllig C, Einsele H, Matsumoto M, Wu KL, Anderson KC, Jou YM, Ganetsky A, Singhal AK, Richardson PG. Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study. Blood Cancer J. 2020 Sep 4;10(9):91. link to original article link to PMC article PubMed

Elo-Vd

Elo-Vd: Elotuzumab, Velcade (Bortezomib), low-dose dexamethasone
EBd: Elotuzumab, Bortezomib, low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jakubowiak et al. 2016 (CA204-009)	2012-2013	Randomized Phase 2 (E-esc)	Vd	Might have superior PFS (primary endpoint) (HR 0.72, 95% CI 0.49-1.06)

Prior treatment criteria

• CA204-009: 1 to 3 prior lines of therapy

Targeted therapy

• Elotuzumab (Empliciti) as follows:
  • Cycles 1 & 2: 10 mg/kg IV once per day on days 1, 8, 15
  • Cycles 3 to 8: 10 mg/kg IV once per day on days 1 & 11
  • Cycle 9 onwards: 10 mg/kg IV once per day on days 1 & 15
• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² IV or SC once per day on days 1, 4, 8, 11
  • Cycle 9 onwards: 1.3 mg/m² IV or SC once per day on days 1, 8, 15

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 2 by the following split schedule:
    • 20 mg PO once per day on days 2, 4, 5, 9, 11, 12
    • 8 mg PO once per day on days 1, 8, 15, given 3 to 24 hours prior to elotuzumab
    • 8 mg IV once per day on days 1, 8, 15, given 45 minutes prior to elotuzumab
  • Cycles 3 to 8 by the following split schedule:
    • 20 mg PO once per day on days 2, 4, 5, 8, 9, 12
    • 8 mg PO once per day on days 1 & 11, given 3 to 24 hours prior to elotuzumab
    • 8 mg IV once per day on days 1 & 11, given 45 minutes prior to elotuzumab
  • Cycle 9 onwards by the following split schedule:
    • 20 mg PO once per day on days 2, 8, 9, 16
    • 8 mg PO once per day on days 1 & 15, given 3 to 24 hours prior to elotuzumab
    • 8 mg IV once per day on days 1 & 15, given 45 minutes prior to elotuzumab

Supportive therapy

• Diphenhydramine (Benadryl) 25 to 50 mg (route not specified) once per infusion, 30 to 90 minutes prior to elotuzumab
• Ranitidine (Zantac) 50 mg (route not specified) once per infusion, 30 to 90 minutes prior to elotuzumab
• Acetaminophen (Tylenol) 650 to 1000 mg PO once per infusion, 30 to 90 minutes prior to elotuzumab

21-day cycle for 8 cycles, then 28-day cycles

References

1. CA204-009: Jakubowiak A, Offidani M, Pégourie B, De La Rubia J, Garderet L, Laribi K, Bosi A, Marasca R, Laubach J, Mohrbacher A, Carella AM, Singhal AK, Tsao LC, Lynch M, Bleickardt E, Jou YM, Robbins M, Palumbo A. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood. 2016 Jun 9;127(23):2833-40. Epub 2016 Apr 18. link to original article dosing details in supplement have been reviewed by our editors link to PMC article PubMed NCT01478048

FRD

FRD: Farydak (Panobinostat), Revlimid (Lenalidomide), Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Chari et al. 2017 (GCO 12-0469)	2012 to not reported	Phase 2

Targeted therapy

• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 15, 17, 19
• 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

28-day cycles

References

1. GCO 12-0469: Chari A, Cho HJ, Dhadwal A, Morgan G, La L, Zarychta K, Catamero D, Florendo E, Stevens N, Verina D, Chan E, Leshchenko V, Laganà A, Perumal D, Mei AH, Tung K, Fukui J, Jagannath S, Parekh S. A phase 2 study of panobinostat with lenalidomide and weekly dexamethasone in myeloma. Blood Adv. 2017 Aug 21;1(19):1575-1583. eCollection 2017 Aug 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01651039

IRd

IRd: Ixazomib, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moreau et al. 2016 (TOURMALINE-MM1)	2012-2014	Phase 3 (E-RT-esc)	Rd	Superior PFS (primary endpoint) Median PFS: 20.6 vs 14.7 mo (HR 0.74, 95% CI 0.59-0.94)
Hou et al. 2017 (TOURMALINE-MM1 China Continuation)	2014-05-08 to 2015-05-08	Phase 3 (E-esc)	Rd	Superior OS (secondary endpoint) Median OS: 25.8 vs 15.8 mo (HR 0.42, 95% CI 0.24-0.73) Seems to have superior PFS (primary endpoint) Median PFS: 6.7 vs 4 mo (HR 0.60, 95% CI 0.37-0.97)

Prior treatment criteria

• TOURMALINE-MM1 & TOURMALINE-MM1 China Continuation: 1 to 3 prior lines of therapy

Targeted therapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15, taken at least one hour before or at least two hours after food
• Lenalidomide (Revlimid) by the following renal function-based criteria:
  • Normal renal function: 25 mg PO once per day on days 1 to 21
  • CrCl 60 mL/min/1.73 m² or less OR 50 mL/min/1.73 m² or less (depends on local practice): 10 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

• Thromboprophylaxis required

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rodriguez-Otero et al. 2023 (KarMMa-3)	2019-05 to 2022-04	Phase 3 (C)	Ide-cel	Inferior PFS

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) 20 to 40 mg (route not specified) once per day on days 1, 8, 15, 22

28-day cycles

References

1. TOURMALINE-MM1: Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Simpson DR, Gimsing P, Palumbo A, Garderet L, Cavo M, Kumar S, Touzeau C, Buadi FK, Laubach JP, Berg DT, Lin J, Di Bacco A, Hui AM, van de Velde H, Richardson PG; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016 Apr 28;374(17):1621-1634. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01564537
   1. Subgroup analysis: Avet-Loiseau H, Bahlis NJ, Chng WJ, Masszi T, Viterbo L, Pour L, Ganly P, Palumbo A, Cavo M, Langer C, Pluta A, Nagler A, Kumar S, Ben-Yehuda D, Rajkumar SV, San-Miguel J, Berg D, Lin J, van de Velde H, Esseltine DL, di Bacco A, Moreau P, Richardson PG. Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients. Blood. 2017 Dec 14;130(24):2610-2618. Epub 2017 Oct 20. link to original article PubMed
   2. Update: Richardson PG, Kumar SK, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, Sandhu I, Ganly P, Baker BW, Jackson SR, Stoppa AM, Gimsing P, Garderet L, Touzeau C, Buadi FK, Laubach JP, Cavo M, Darif M, Labotka R, Berg D, Moreau P. Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma. J Clin Oncol. 2021 Aug 1;39(22):2430-2442. Epub 2021 Jun 11. link to original article PubMed
2. TOURMALINE-MM1 China Continuation: Hou J, Jin J, Xu Y, Wu D, Ke X, Zhou D, Lu J, Du X, Chen X, Li J, Liu J, Gupta N, Hanley MJ, Li H, Hua Z, Wang B, Zhang X, Wang H, van de Velde H, Richardson PG, Moreau P. Randomized, double-blind, placebo-controlled phase III study of ixazomib plus lenalidomide-dexamethasone in patients with relapsed/refractory multiple myeloma: China Continuation study. J Hematol Oncol. 2017 Jul 6;10(1):137. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed NCT01564537
3. KarMMa-3: Rodriguez-Otero P, Ailawadhi S, Arnulf B, Patel K, Cavo M, Nooka AK, Manier S, Callander N, Costa LJ, Vij R, Bahlis NJ, Moreau P, Solomon SR, Delforge M, Berdeja J, Truppel-Hartmann A, Yang Z, Favre-Kontula L, Wu F, Piasecki J, Cook M, Giralt S. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2023 Mar 16;388(11):1002-1014. Epub 2023 Feb 10. link to original article dosing details in supplement have been reviewed by our editors PubMed NCT03651128
   1. PRO analysis: Delforge M, Patel K, Eliason L, Dhanda D, Shi L, Guo S, Marshall TS, Arnulf B, Cavo M, Nooka A, Manier S, Callander N, Giralt S, Einsele H, Ailawadhi S, Popa McKiver M, Cook M, Rodríguez-Otero P. Health-related quality of life in patients with triple-class exposed relapsed and refractory multiple myeloma treated with idecabtagene vicleucel or standard regimens: patient-reported outcomes from the phase 3, randomised, open-label KarMMa-3 clinical trial. Lancet Haematol. 2024 Mar;11(3):e216-e227. link to original article PubMed

Isa-Kd

Isa-Kd: Isatuximab, Kyprolis (Carfilzomib), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Moreau et al. 2021 (IKEMA)	2017-11-15 to 2019-03-21	Phase 3 (E-RT-esc)	Kd	Superior PFS1 (primary endpoint) Median PFS: 35.7 vs 19.2 mo (HR 0.58, 99% CI 0.42-0.79)

¹Reported efficacy is based on the 2023 update.

Prior treatment criteria

• 1 to 3 prior lines of therapy

Targeted therapy

• Isatuximab (Sarclisa) given second as follows:
  • Cycle 1: 10 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycle 2 onwards: 10 mg/kg IV once per day on days 1 & 15
• Carfilzomib (Kyprolis) given third as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1 & 2, then 56 mg/m² IV once per day on days 8, 9, 15, 16
  • Cycle 2 onwards: 56 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO or IV once per day on days 1, 2, 8, 9, 15, 16, 22, 23, given first

28-day cycles

References

1. IKEMA: Moreau P, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Risse ML, Asset G, Macé S, Martin T; IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021 Jun 19;397(10292):2361-2371. Epub 2021 Jun 4. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03275285
   1. Update: Martin T, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Casca F, Macé S, Risse ML, Moreau P. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. 2023 May 9;13(1):72. Erratum in: Blood Cancer J. 2023 Sep 27;13(1):152. link to original article link to PMC article PubMed
   2. Update: Yong K, Martin T, Dimopoulos MA, Mikhael J, Capra M, Facon T, Hajek R, Špička I, Baker R, Kim K, Martinez G, Min CK, Pour L, Leleu X, Oriol A, Koh Y, Suzuki K, Casca F, Macé S, Risse ML, Moreau P. Isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma (IKEMA): overall survival analysis of a phase 3, randomised, controlled trial. Lancet Haematol. 2024 Oct;11(10):e741-e750. Epub 2024 Jul 24. link to original article PubMed

Isa-Pd

Isa-Pd: Isatuximab, Pomalidomide, low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Attal et al. 2019 (ICARIA-MM)	2017-01-10 to 2018-02-02	Phase 3 (E-RT-esc)	Pd	Might have superior OS1 (secondary endpoint) Median OS: 24.6 vs 17.7 mo (HR 0.78, 95% CI 0.59-1.02) Superior PFS (primary endpoint) Median PFS: 11.5 vs 6.5 mo (HR 0.60, 95% CI 0.44-0.81)

¹Reported efficacy is based on the 2024 update.

Prior treatment criteria

• ICARIA-MM: At least 2 prior lines of therapy including lenalidomide and a proteasome inhibitor

Targeted therapy

• Isatuximab (Sarclisa) as follows:
  • Cycle 1: 10 mg/kg IV once per day on days 1, 8, 15, 22
  • Cycle 2 onwards: 10 mg/kg IV once per day on days 1 & 15
• Pomalidomide (Pomalyst) 4 mg PO once per 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

Supportive therapy

• Mandatory Aspirin or |LMWH

28-day cycles

References

1. ICARIA-MM: Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Macé S, Corzo KP, Campana F, Le-Guennec S, Dubin F, Anderson KC; ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019 Dec 7;394(10214):2096-2107. Epub 2019 Nov 14. Erratum in: Lancet. 2019 Dec 7;394(10214):2072. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02990338
   1. Update: Richardson PG, Perrot A, San-Miguel J, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang JS, Minarik J, Cavo M, Prince HM, Malinge L, Dubin F, van de Velde H, Anderson KC. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022 Mar;23(3):416-427. Epub 2022 Feb 10. link to original article PubMed
   2. Update: Richardson PG, Perrot A, Miguel JS, Beksac M, Spicka I, Leleu X, Schjesvold F, Moreau P, Dimopoulos MA, Huang SY, Minarik J, Cavo M, Prince HM, Macé S, Zhang R, Dubin F, Morisse MC, Anderson KC. Isatuximab-pomalidomide-dexamethasone versus pomalidomide-dexamethasone in patients with relapsed and refractory multiple myeloma: final overall survival analysis. Haematologica. 2024 Jul 1;109(7):2239-2249. link to original article link to PMC article PubMed
2. EFC15951: NCT05405166

KPD

KPD: Kyprolis (Carfilzomib), Pomalidomide, Dexamethasone
CPD: Carfilzomib, Pomalidomide, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Shah et al. 2015 (PO-MM-PI-0034)	2011 to not reported	Phase 1

Note: although this is described as a Phase 1 trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once per day on days 1 & 2, then 27 mg/m² IV over 30 minutes once per day on days 8, 9, 15, 16
  • Cycles 2 to 6: 27 mg/m² IV over 30 minutes once per day on days 1, 2, 8, 9, 15, 16
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 40 mg IV or PO once per day on days 1, 8, 15, 22
  • Cycles 5 to 6: 20 mg IV or PO once per day on days 1, 8, 15, 22

Supportive therapy

• "Anti-viral therapy"
• Aspirin 81 mg PO once per day
  • Low molecular weight heparin was used in patients intolerant of aspirin

28-day cycle for 6 cycles

Subsequent treatment

• KPD maintenance

References

1. PO-MM-PI-0034: Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01464034

KRd

KRd: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), low-dose dexamethasone
CRd: Carfilzomib, Revlimid (Lenalidomide), low-dose dexamethasone

Regimen variant #1, bi-weekly carfilzomib x 48 weeks ("KRd27")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Dimopoulos et al. 2024 (ARROW2)	2019-05 to 2022-02	Phase 3 (C)	KRd; weekly x 48 weeks	Did not meet primary endpoint of ORR ORR: 86.3% vs 82.5%

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 10 minutes once per day on days 1 & 2, then 27 mg/m² IV over 10 minutes once per day on days 8, 9, 15, 16
  • Cycles 2 to 12: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 9: 40 mg PO or IV once per day on days 1, 8, 15, 22
  • Cycles 10 to 12: 40 mg PO or IV once per day on days 1, 8, 15

28-day cycle for 12 cycles

Regimen variant #2, bi-weekly carfilzomib x 72 weeks ("KRd27")

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Wang et al. 2013 (PX-171-006)	2008-2010	Phase 2
Stewart et al. 2014 (ASPIRE)	2010-2012	Phase 3 (E-RT-esc)	Rd	Superior PFS (primary endpoint) Median PFS: 26.3 vs 17.6 mo (HR 0.69, 95% CI 0.57-0.83) Superior OS1 (secondary endpoint) (HR 0.79, 95% CI 0.67-0.95)	Superior GHS/QoL

¹Reported efficacy for ASPIRE is based on the 2018 update.
Note: In PX-171-006, patients with at least SD after 4 cycles received up to 12 cycles; patients with at least SD after 12 cycles received up to 18 cycles.

Prior treatment criteria

• ASPIRE: 1 to 3 prior lines of therapy

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 10 minutes once per day on days 1 & 2, then 27 mg/m² IV over 10 minutes once per day on days 8, 9, 15, 16
  • Cycles 2 to 12: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 8, 9, 15, 16
  • Cycles 13 to 18: 27 mg/m² IV over 10 minutes once per day on days 1, 2, 15, 16
• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

Glucocorticoid therapy

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

Supportive therapy

• Valacyclovir (Valtrex) (dose not specified) or equivalent antiviral while taking Lenalidomide (Revlimid)
• Aspirin (dose not specified) or other anticoagulant or antiplatelet medication such as Clopidogrel (Plavix), low-molecular-weight heparin or Warfarin (Coumadin) while taking Lenalidomide (Revlimid)
• Bisphosphonates while taking Dexamethasone (Decadron)
• Lansoprazole (Prevacid) (dose not specified) or other proton pump inhibitor while taking Dexamethasone (Decadron)
• A prophylactic antibiotic (Ciprofloxacin (Cipro), Amoxicillin, Trimethoprim-Sulfamethoxazole (Bactrim DS) are given as examples)

28-day cycle for 18 cycles

Subsequent treatment

• ASPIRE, no progression: Rd maintenance

Regimen variant #3, weekly carfilzomib x 72 weeks ("KRd56")

Study	Dates of enrollment	Evidence
Biran et al. 2019 (CFZ013)	2015-2016	Phase 1b

Note: this is the dose that is being explored in phase 3 studies.

Targeted therapy

• 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 18: 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 8: 40 mg PO once per day on days 1, 8, 15, 22
  • Cycles 9 to 18: 40 mg PO once per day on days 1, 8, 15

28-day cycle for up to 18 cycles

References

1. PX-171-006: Wang M, Martin T, Bensinger W, Alsina M, Siegel DS, Kavalerchik E, Huang M, Orlowski RZ, Niesvizky R. Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013 Oct 31;122(18):3122-8. Epub 2013 Sep 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00603447
2. ASPIRE: Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Mihaylov GG, Goranova-Marinova V, Rajnics P, Suvorov A, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Wang M, Maisnar V, Minarik J, Bensinger WI, Mateos MV, Ben-Yehuda D, Kukreti V, Zojwalla N, Tonda ME, Yang X, Xing B, Moreau P, Palumbo A; ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015 Jan 8;372(2):142-52. Epub 2014 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01080391
   1. Subgroup analysis: Avet-Loiseau H, Fonseca R, Siegel D, Dimopoulos MA, Špička I, Masszi T, Hájek R, Rosiñol L, Goranova-Marinova V, Mihaylov G, Maisnar V, Mateos MV, Wang M, Niesvizky R, Oriol A, Jakubowiak A, Minarik J, Palumbo A, Bensinger W, Kukreti V, Ben-Yehuda D, Stewart AK, Obreja M, Moreau P. Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma. Blood. 2016 Sep 1;128(9):1174-80. Epub 2016 Jul 20. link to original article link to PMC article PubMed
   2. HRQoL analysis: Stewart AK, Dimopoulos MA, Masszi T, Špička I, Oriol A, Hájek R, Rosiñol L, Siegel DS, Niesvizky R, Jakubowiak AJ, San-Miguel JF, Ludwig H, Buchanan J, Cocks K, Yang X, Xing B, Zojwalla N, Tonda M, Moreau P, Palumbo A. Health-related quality-of-life results from the open-label, randomized, phase III ASPIRE trial evaluating carfilzomib, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma. J Clin Oncol. 2016 Nov 10;34(32):3921-3930. link to original article link to PMC article PubMed
   3. Update: Siegel DS, Dimopoulos MA, Ludwig H, Facon T, Goldschmidt H, Jakubowiak A, San-Miguel J, Obreja M, Blaedel J, Stewart AK. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018 Mar 10;36(8):728-734. Epub 2018 Jan 17. link to original article PubMed
3. CFZ013: Biran N, Siegel D, Berdeja JG, Raje N, Cornell RF, Alsina M, Kovacsovics T, Fang B, Kimball AS, Landgren O. Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a phase 1b study. Am J Hematol. 2019 Jul;94(7):794-802. Epub 2019 May 13. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02335983
4. ARROW2: Dimopoulos MA, Coriu D, Delimpasi S, Špička I, Upchurch T, Fang B, Talpur R, Faber E, Beksac M, Leleu X. ARROW2: once- vs twice-weekly carfilzomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma. Blood Adv. 2024 Oct 8;8(19):5012-5021. link to original article PubMed NCT03859427

PAD

PAD: PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone
Note that this regimen is sometimes called VAD but this can create a lot of confusion with the "original" VAD which uses Vincristine.
VAD: Velcade (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Cook et al. 2014 (NCRI Myeloma X Relapse)	2008-2012	Non-randomized part of phase 3 RCT

Note: length of cycle is not reported in the manuscript, but presumably is 28 days, similar to other PAD regimens.

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
  • Could be given as a 4-day continuous infusion or as bolus injections

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

28-day cycle for 2 to 4 cycles

Subsequent treatment

• High-dose melphalan & autologous hematopoietic cell transplant consolidation versus weekly oral cyclophosphamide maintenance

References

1. NCRI Myeloma X Relapse: Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. link to original article PubMed NCT00747877
   1. Update: Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. link to original article dosing details in abstract have been reviewed by our editors PubMed
   2. Subgroup analysis: Cook G, Royle KL, O'Connor S, Cairns DA, Ashcroft AJ, Williams CD, Hockaday A, Cavenagh JD, Snowden JA, Ademokun D, Tholouli E, Andrews VE, Jenner M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Drayson MT, Brown JM, Morris TCM; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Br J Haematol. 2019 May;185(3):450-467. Epub 2019 Feb 6. link to original article link to PMC article PubMed

PCD

PCD: Pomalidomide, Cyclophosphamide, Dexamethasone
PomCyDex: Pomalidomide, Cyclophosphamide, Dexamethasone

Regimen variant #1, 4/300/40

Study	Dates of enrollment	Evidence
Garderet et al. 2018 (IC 2013-05)	2014-2017	Phase 2

Targeted therapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg PO once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 40 mg PO once per day on days 1 to 4, 15 to 18
  • Cycles 5 to 9: 40 mg PO once per day on days 1, 8, 15, 22

28-day cycle for 4 to 9 cycles, depending on plan for transplant

Subsequent treatment

• Pd maintenance

Regimen variant #2, 4/400/40

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Baz et al. 2016 (PO-MM-PI-0039)	2011-2014	Randomized Phase 1/2 (E-esc)	Pd	Seems to have superior ORR (primary endpoint)

Prior treatment criteria

• PO-MM-PI-0039: At least 2 prior lines of therapy including an immunomodulator; patients were required to be lenalidomide-refractory

Targeted therapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Chemotherapy

• Cyclophosphamide (Cytoxan) 400 mg PO once per day on days 1, 8, 15

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

Supportive therapy

• Aspirin 81 mg PO once per day unless contraindicated

28-day cycles

References

1. PO-MM-PI-0039: Baz RC, Martin TG 3rd, Lin HY, Zhao X, Shain KH, Cho HJ, Wolf JL, Mahindra A, Chari A, Sullivan DM, Nardelli LA, Lau K, Alsina M, Jagannath S. Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma. Blood. 2016 May 26;127(21):2561-8. Epub 2016 Mar 1. Erratum in: Blood. 2016 Jul 21;128(3):461. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01432600
2. IC 2013-05: Garderet L, Kuhnowski F, Berge B, Roussel M, Escoffre-Barbe M, Lafon I, Facon T, Leleu X, Karlin L, Perrot A, Moreau P, Marit G, Stoppa AM, Royer B, Chaleteix C, Tiab M, Araujo C, Lenain P, Macro M, Voog E, Benboubker L, Allangba O, Jourdan E, Orsini-Piocelle F, Brechignac S, Eveillard JR, Belhadj K, Wetterwald M, Pegourie B, Jaccard A, Eisenmann JC, Glaisner S, Mohty M, Hulin C, Loiseau HA, Mathiot C, Attal M. Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma. Blood. 2018 Dec 13;132(24):2555-2563. Epub 2018 Oct 3. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02244125

PCP

PCP: Pomalidomide, Cyclophosphamide, Prednisone

Regimen

Study	Dates of enrollment	Evidence
Larocca et al. 2013 (PO0023)	2010-2012	Phase 1/2

Note: Details are for the phase 2 portion of the published phase 1/2 trial.

Targeted therapy

• Pomalidomide (Pomalyst) 2.5 mg PO once per day

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once every other day

Glucocorticoid therapy

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

Supportive therapy

• Aspirin 100 mg PO once per day or low-molecular-weight heparin "according to patient risk"

28-day cycle for 6 cycles

Subsequent treatment

• Pomalidomide & prednisone maintenance

References

1. PO0023: Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01166113

PVD

PVD: Pomalidomide, Velcade (Bortezomib), Dexamethasone
PVd: Pomalidomide, Velcade (Bortezomib), low-dose dexamethasone

Regimen variant #1, 21-day cycles, 75 years old and younger

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2019 (OPTIMISMM)	2013-2017	Phase 3 (E-esc)	Vd	Superior PFS (primary endpoint) Median PFS: 11.2 vs 7.1 mo (HR 0.61, 95% CI 0.49-0.77)
San-Miguel et al. 2023 (CARTITUDE-4)	2020-07-10 to 2021-11-17	Phase 3 (C)	Cilta-cel	Inferior PFS
Dimopoulos et al. 2024 (DREAMM-8)	2020-10 to 2022-12	Phase 3 (C)	BPd	Inferior PFS

Note: CARTITUDE-4 only used the SC route for bortezomib.

Prior treatment criteria

• OPTIMISMM: 1 to 3 prior lines of therapy including lenalidomide
• DREAMM-8: At least 1 prior line of therapy

Targeted therapy

• Pomalidomide (Pomalyst) 4 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
  • Cycle 9 onwards: 1.3 mg/m² IV or SC once per day on days 1 & 8

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycle 9 onwards: 20 mg PO once per day on days 1, 2, 8, 9

21-day cycles

Regimen variant #2, 21-day cycles, older than 75 years old

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2019 (OPTIMISMM)	2013-2017	Phase 3 (E-esc)	Vd	Superior PFS (primary endpoint) Median PFS: 11.2 vs 7.1 mo (HR 0.61, 95% CI 0.49-0.77)

Prior treatment criteria

• 1 to 3 prior lines of therapy including lenalidomide

Targeted therapy

• Pomalidomide (Pomalyst) 4 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
  • Cycle 9 onwards: 1.3 mg/m² IV or SC once per day on days 1 & 8

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 8: 10 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycle 9 onwards: 10 mg PO once per day on days 1, 2, 8, 9

21-day cycles

Regimen variant #3, 28-day cycles

Study	Dates of enrollment	Evidence	Efficacy
Paludo et al. 2017 (MC1082)	2012-2014	Phase 1/2	ORR: 86%

Note: This is the MTD used in the phase 2 portion of the trial.

Targeted therapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21
• Bortezomib (Velcade) 1.3 mg/m² IV or SC once per day on days 1, 8, 15, 22

Glucocorticoid therapy

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

Supportive therapy

• Aspirin 325 mg PO once per day
  • Full dose anticoagulation with LMWH or Warfarin (Coumadin) could be substituted at physician discretion
• Acyclovir (Zovirax) or equivalent for VZV prophylaxis

28-day cycle for 8 cycles

Subsequent treatment

• Optionally, pomalidomide maintenance

References

1. MC1082: Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. Epub 2017 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01212952
2. OPTIMISMM: Richardson PG, Oriol A, Beksac M, Liberati AM, Galli M, Schjesvold F, Lindsay J, Weisel K, White D, Facon T, San Miguel J, Sunami K, O'Gorman P, Sonneveld P, Robak P, Semochkin S, Schey S, Yu X, Doerr T, Bensmaine A, Biyukov T, Peluso T, Zaki M, Anderson K, Dimopoulos M; OPTIMISMM trial investigators. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019 Jun;20(6):781-794. Epub 2019 May 13. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01734928
3. CARTITUDE-4: San-Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV, Fernández de Larrea C, Martínez-López J, Moreau P, Touzeau C, Leleu X, Avivi I, Cavo M, Ishida T, Kim SJ, Roeloffzen W, van de Donk NWCJ, Dytfeld D, Sidana S, Costa LJ, Oriol A, Popat R, Khan AM, Cohen YC, Ho PJ, Griffin J, Lendvai N, Lonardi C, Slaughter A, Schecter JM, Jackson CC, Connors K, Li K, Zudaire E, Chen D, Gilbert J, Yeh TM, Nagle S, Florendo E, Pacaud L, Patel N, Harrison SJ, Einsele H. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. N Engl J Med. 2023 Jul 27;389(4):335-347. Epub 2023 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT04181827
4. DREAMM-8: Dimopoulos MA, Beksac M, Pour L, Delimpasi S, Vorobyev V, Quach H, Spicka I, Radocha J, Robak P, Kim K, Cavo M, Suzuki K, Morris K, Pompilus F, Phillips-Jones A, Zhou XL, Fulci G, Sule N, Kremer BE, Opalinska J, Mateos MV, Trudel S; DREAMM-8 Investigators. Belantamab Mafodotin, Pomalidomide, and Dexamethasone in Multiple Myeloma. N Engl J Med. 2024 Aug 1;391(5):408-421. Epub 2024 Jun 2. link to original article dosing details in protocol have been reviewed by our editors PubMed NCT04484623

RVD

RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Richardson et al. 2014 (DFCI 06-147)	2006-2008	Phase 2	ORR: 64%

Targeted therapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
• Bortezomib (Velcade) 1 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 for VZV prophylaxis

21-day cycle for 8 cycles

Subsequent treatment

• DFCI 06-147, patients with SD or better: RVD maintenance at previously tolerated dose

References

1. DFCI 06-147: Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00378209

SDd

SDd: Selinexor, Daratumumab, low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Gasparetto et al. 2020 (STOMP)	2017-2019	Phase 1/2b, >20 pts in this cohort

Note: this is the dosing used in the expansion cohort.

Targeted therapy

• Selinexor (Xpovio) 100 mg PO once per day on days 1, 8, 15, 22
• 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

Glucocorticoid therapy

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

28-day cycles

References

1. STOMP: Gasparetto C, Lentsch S, Schiller G, Callander N, Tuchman S, Chen C, White D, Kotb R, Sutherland H, Sebag M, Baljevic M, Bensinger W, LeBlanc R, Venner C, Bahlis N, Rossi A, Biran N, Sheehan H, Saint Martin JR, Van Domelen D, Kai K, Shah J, Shacham S, Kauffman M, Lipe B. Selinexor, daratumumab, and dexamethasone in patients with relapsed or refractory multiple myeloma. eJHaem. 2020 Nov 8;2(1):56-65. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT02343042

SKd

SKd: Selinexor, Kyprolis (Carfilzomib), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Jakubowiak et al. 2019	2014-2016	Phase 1, fewer than 20 pts in this cohort

Note: this is the RP2D cohort (2b).

Targeted therapy

• Selinexor (Xpovio) 60 mg PO once per day on days 1, 3, 8, 10, 15, 17
• 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 8: 27 mg/m² IV once per day on days 1, 2, 8, 9, 15, 16
  • Cycle 9 onwards: 27 mg/m² IV once per day on days 1, 2, 15, 16

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 4: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23
  • Cycle 5 onwards: 10 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

28-day cycles

References

1. Jakubowiak AJ, Jasielec JK, Rosenbaum CA, Cole CE, Chari A, Mikhael J, Nam J, McIver A, Severson E, Stephens LA, Tinari K, Rosebeck S, Zimmerman TM, Hycner T, Turowski A, Karrison T, Zonder JA. Phase 1 study of selinexor plus carfilzomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma. Br J Haematol. 2019 Aug;186(4):549-560. Epub 2019 May 24. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02199665

SVd

SVd: Selinexor, Velcade (Bortezomib), low-dose dexamethasone
XVd: Xpovio (Selinexor), Velcade (Bortezomib), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Grosicki et al. 2020 (BOSTON)	2017-2019	Phase 3 (E-RT-esc)	Vd	Superior PFS (primary endpoint) Median PFS: 13.9 vs 9.5 mo (HR 0.70, 95% CI 0.53-0.93)

Prior treatment criteria

• 1 to 3 prior lines of therapy, including proteasome inhibitors

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1, 8, 15, 22
• Selinexor (Xpovio) 100 mg PO once per day on days 1, 8, 15, 22, 29

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23, 29, 30

35-day cycles

References

1. BOSTON: Grosicki S, Simonova M, Spicka I, Pour L, Kriachok I, Gavriatopoulou M, Pylypenko H, Auner HW, Leleu X, Doronin V, Usenko G, Bahlis NJ, Hajek R, Benjamin R, Dolai TK, Sinha DK, Venner CP, Garg M, Gironella M, Jurczyszyn A, Robak P, Galli M, Wallington-Beddoe C, Radinoff A, Salogub G, Stevens DA, Basu S, Liberati AM, Quach H, Goranova-Marinova VS, Bila J, Katodritou E, Oliynyk H, Korenkova S, Kumar J, Jagannath S, Moreau P, Levy M, White D, Gatt ME, Facon T, Mateos MV, Cavo M, Reece D, Anderson LD Jr, Saint-Martin JR, Jeha J, Joshi AA, Chai Y, Li L, Peddagali V, Arazy M, Shah J, Shacham S, Kauffman MG, Dimopoulos MA, Richardson PG, Delimpasi S. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial. Lancet. 2020 Nov 14;396(10262):1563-1573. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT03110562
2. BENCH: NCT04939142

VDC

VDC: Velcade (Bortezomib), Dexamethasone, Cyclophosphamide
VCD: Velcade (Bortezomib), Cyclophosphamide, Dexamethasone
CyBorD: Cyclophosphamide, Bortezomib, Dexamethasone

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kropff et al. 2017 (CR015247)	2008-2010	Phase 3 (E-esc)	Vd	Did not meet primary endpoint of TTP (HR 1.41, 95% CI 0.84-2.33)

Note: Treatment details are from the CT.gov record. This is an experimental arm that did not meet its primary endpoint.

Prior treatment criteria

• 1 to 3 prior lines of therapy

Targeted therapy

• 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

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day

21-day cycle for up to 8 cycles

Regimen variant #2

Study	Dates of enrollment	Evidence
de Waal et al. 2015	2009-2013	Phase 2

Prior treatment criteria

• Bortezomib-naive

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 3: 1.3 mg/m² IV or SC once per day on days 1, 4, 8, 11
  • Cycles 4 to 6: 1.6 mg/m² IV or SC once per day on days 1, 8, 15, 22

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day

Supportive therapy

• Pneumococccal and anti-fungal prophylaxis "according to local protocols"
• Valacyclovir (Valtrex) (dose not specified) for herpes prophylaxis

21-day cycle for 3 cycles then 35-day cycle for 3 cycles

Subsequent treatment

• de Waal et al. 2015, patients with PR/CR: Bortezomib & cyclophosphamide maintenance

Regimen variant #3

Study	Dates of enrollment	Evidence
Kropff et al. 2007	2004-2005	Phase 2

Prior treatment criteria

• Bortezomib-naive

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 3: 1.3 mg/m² IV once per day on days 1, 4, 8, 11
  • Cycles 4 to 6: 1.3 mg/m² IV once per day on days 1, 8, 15, 22

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 to 3: 20 mg PO once per day on days 1, 2, 4, 5, 8, 9, 11, 12
  • Cycles 4 to 6: 20 mg PO once per day on days 1, 2, 8, 9, 15, 16, 22, 23

21-day cycle for 3 cycles then 35-day cycle for 3 cycles

References

1. Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom,. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007 Aug;138(3):330-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed
3. CR015247: Kropff M, Vogel M, Bisping G, Schlag R, Weide R, Knauf W, Fiechtner H, Kojouharoff G, Kremers S, Berdel WE. Bortezomib and low-dose dexamethasone with or without continuous low-dose oral cyclophosphamide for primary refractory or relapsed multiple myeloma: a randomized phase III study. Ann Hematol. 2017 Nov;96(11):1857-1866. Epub 2017 Sep 14. link to original article PubMed NCT00813150

VTD

VTD: Velcade (Bortezomib), Thalidomide, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Garderet et al. 2012 (MMVAR/IFM 2005-04)	2006-2010	Phase 3 (E-esc)	TD	Superior TTP (primary endpoint) Median TTP: 19.5 vs 13.8 mo (HR 0.59, 95% CI 0.44-0.80)

Prior treatment criteria

• At least 1 autologous stem-cell transplant

Targeted therapy

• Bortezomib (Velcade) as follows:
  • Cycles 1 to 8: 1.3 mg/m² IV bolus once per day on days 1, 4, 8, 11
  • Cycles 9 to 12: 1.3 mg/m² IV bolus once per day on days 1, 8, 15, 22
• Thalidomide (Thalomid) 200 mg PO once per day

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive therapy

• Primary prophylaxis: Enoxaparin (Lovenox) 40 mg SC once per day
• Secondary prophylaxis: Warfarin (Coumadin)
• Herpes zoster prophylaxis highly recommended

21-day cycle for 8 cycles, then 42-day cycle for 4 cycles (1 year)

References

1. MMVAR/IFM 2005-04: Garderet L, Iacobelli S, Moreau P, Dib M, Lafon I, Niederwieser D, Masszi T, Fontan J, Michallet M, Gratwohl A, Milone G, Doyen C, Pegourie B, Hajek R, Casassus P, Kolb B, Chaleteix C, Hertenstein B, Onida F, Ludwig H, Ketterer N, Koenecke C, van Os M, Mohty M, Cakana A, Gorin NC, de Witte T, Harousseau JL, Morris C, Gahrton G. Superiority of the triple combination of bortezomib-thalidomide-dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 randomized phase III trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012 Jul 10;30(20):2475-82. Epub 2012 May 14. Erratum in: J Clin Oncol. 2012 Sep 20;30(27):3429. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00256776

Ven-Kd

Ven-Kd: Venetoclax, Kyprolis (Carfilzomib), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Costa et al. 2021 (M15-538)	2017-02 to 2019-02	Phase 2

Note: this was the dosing used in the dose expansion cohort.

Targeted therapy

• Venetoclax (Venclexta) 800 mg PO once per day on days 1 to 28
• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV over 30 minutes once on day 1, then 70 mg/m² IV over 30 minutes once per day on days 8 & 15
  • Cycle 2 onwards: 70 mg/m² IV over 30 minutes 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 cycles

References

1. M15-538: Costa LJ, Davies FE, Monohan GP, Kovacsovics T, Burwick N, Jakubowiak A, Kaufman JL, Hong WJ, Dail M, Salem AH, Yang X, Masud AA, Munasinghe W, Ross JA, Bueno OF, Kumar SK, Stadtmauer EA. Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Blood Adv. 2021 Oct 12;5(19):3748-3759. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02899052

ZRd

ZRd: Zolinza (Vorinostat), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Sanchez et al. 2016 (PRO-2580)	2012-2014	Phase 2b

Targeted therapy

• Vorinostat (Zolinza) 400 mg PO once per day on days 1 to 7, 15 to 21
• 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 cycles

References

1. PRO-2580: Sanchez L, Vesole DH, Richter JR, Biran N, Bilotti E, McBride L, Anand P, Ivanovski K, Siegel DS. A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide-containing regimens. Br J Haematol. 2017 Feb;176(3):440-447. Epub 2016 Nov 18. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01502085

Relapsed or refractory, other combinations

Bortezomib, Thalidomide, Dexamethasone, Panobinostat

Regimen

Study	Dates of enrollment	Evidence
Popat et al. 2016 (MUK-six)	2013-2014	Phase 1/2

Note: this is the dose used in the phase 2 portion of the trial.

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1 & 8
• Thalidomide (Thalomid) 100 mg PO once per day
• Panobinostat (Farydak) 20 mg PO once per day on days 1, 3, 5, 8, 10, 12

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg PO once per day on days 1, 2, 8, 9

21-day cycle for 16 cycles

References

1. MUK-six: Popat R, Brown SR, Flanagan L, Hall A, Gregory W, Kishore B, Streetly M, Oakervee H, Yong K, Cook G, Low E, Cavenagh J; Myeloma UK Early Phase Clinical Trial Network.. Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. Lancet Haematol. 2016 Dec;3(12):e572-e580. Epub 2016 Nov 12. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02145715

DCEP

DCEP: Dexamethasone, Cyclophosphamide, Etoposide, Platinol (Cisplatin)

Regimen variant #1

Study	Dates of enrollment	Evidence
Lazzarino et al. 2001	2000-2001	Phase 2

Note: this protocol is reported as a mobilization regimen prior to high dose autologous transplant; all patients had received prior therapy.

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 160 mg/m²)
• Cisplatin (Platinol) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 40 mg/m²)

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting 48 hours after chemotherapy and continuing through stem cell collection

One course

Regimen variant #2

Study	Dates of enrollment	Evidence
Dadacaridou et al. 2007	Not reported in abstract	Phase 2, fewer than 20 patients reported

Note: These limited details are based on the abstract's description only. Full article was not available for review.

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg IV bolus once per day on days 1 to 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 160 mg/m²)
• Cisplatin (Platinol) 15 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 60 mg/m²)

Supportive therapy

• G-CSF SC once per day, starting on day 5, to continue until neutrophil recovery

28-day cycles

References

1. Lazzarino M, Corso A, Barbarano L, Alessandrino EP, Cairoli R, Pinotti G, Ucci G, Uziel L, Rodeghiero F, Fava S, Ferrari D, Fiumanò M, Frigerio G, Isa L, Luraschi A, Montanara S, Morandi S, Perego D, Santagostino A, Savarè M, Vismara A, Morra E. DCEP (dexamethasone, cyclophosphamide, etoposide, and cisplatin) is an effective regimen for peripheral blood stem cell collection in multiple myeloma. Bone Marrow Transplant. 2001 Nov;28(9):835-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. Dadacaridou M, Papanicolaou X, Maltesas D, Megalakaki C, Patos P, Panteli K, Repousis P, Mitsouli-Mentzikof C. Dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) for relapsed or refractory multiple myeloma patients. J BUON. 2007 Jan-Mar;12(1):41 to 4. PubMed

DTPACE

DTPACE: Dexamethasone, Thalidomide, Platinol (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide

Regimen

Study	Dates of enrollment	Evidence
Lee et al. 2003 (UARK-98035)	1998-2001	Prospective

Targeted therapy

• Thalidomide (Thalomid) 400 mg PO once per day, taken at night

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Chemotherapy

• Cisplatin (Platinol) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 160 mg/m²)

Supportive therapy

• Filgrastim (Neupogen) 300 mcg SC once per day from day 5 until ANC greater than 1000/ul for two consecutive days
• Levofloxacin (Levaquin) 250 mg PO once per day from day 1 until ANC greater than 1000/ul for two consecutive days
• Fluconazole (Diflucan) 200 mg PO once per day from day 1 until ANC greater than 1000/ul for two consecutive days
• Acyclovir (Zovirax) 400 mg PO twice per day from day 1 until ANC greater than 1000/ul for two consecutive days
• Trimethoprim-Sulfamethoxazole (Bactrim DS) 800/160 mg PO twice per day twice per week

4- to 6-week cycles

References

1. UARK-98035: Lee CK, Barlogie B, Munshi N, Zangari M, Fassas A, Jacobson J, van Rhee F, Cottler-Fox M, Muwalla F, Tricot G. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003 Jul 15;21(14):2732-9. Erratum in: J Clin Oncol. 2008 Apr 20;26(12): 2066. link to original article dosing details in manuscript have been reviewed by our editors PubMed

Hyper-CVAD

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen variant #1

Study	Dates of enrollment	Evidence
Dimopoulos et al. 1996	Not reported	Phase 2

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
• Vincristine (Oncovin) 1 mg/day IV continuous infusion over 48 hours, started on day 4, 12 hours after last dose of cyclophosphamide, then 2 mg IV once on day 11
• Doxorubicin (Adriamycin) 25 mg/m²/day IV continuous infusion over 48 hours, started on day 4, 12 hours after last dose of cyclophosphamide (total dose per cycle: 50 mg/m²)

Glucocorticoid therapy

• Dexamethasone (Decadron) 20 mg/m² PO once per day on days 1 to 5, 11 to 14

Supportive therapy

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m²)
• Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 6 until WBC count more than 2000/μL for 2 consecutive days
• Ciprofloxacin (Cipro) 500 mg PO twice per day on days 8 to 18
• Fluconazole (Diflucan) 100 mg PO once per day on days 8 to 18
• Acyclovir (Zovirax) 200 mg PO three times per day on days 8 to 18

Up to 2 cycles (length not specified)

Subsequent treatment

• Dimopoulos et al. 1996, responding patients: Cyclophosphamide & Dexamethasone maintenance

Regimen variant #2, modified

Study	Dates of enrollment	Evidence
Saraceni et al. 2017	2011-11 to 2015-09	Retrospective

Note: vincristine is a flat dose.

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² IV every 12 hours on days 1 to 4 (total dose per cycle: 2400 mg/m²)
• 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

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 5 or 6
• Mesna (Mesnex) 350 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1400 mg/m²)
• Antiviral prophylaxis with Valacyclovir (Valtrex) daily (dose not specified)
• "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

References

1. Dimopoulos MA, Weber D, Kantarjian H, Delasalle KB, Alexanian R. HyperCVAD for VAD-resistant multiple myeloma. Am J Hematol. 1996 Jun;52(2):77-81. link to original article dosing details in manuscript have been reviewed by our editors PubMed
2. Retrospective: Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E. Modified hyperCVAD versus bortezomib-hyperCAD in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84. Epub 2017 Nov 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed

KD-PACE

KD-PACE: Kyprolis (Carfilzomib), Dexamethasone, Platinol (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide (Toposar)

Regimen

Study	Dates of enrollment	Evidence
Alsouqi et al. 2021	2015-09 to 2018-09	Retrospective

Targeted therapy

• Carfilzomib (Kyprolis) as follows:
  • Cycle 1: 20 mg/m² IV once per day on days 1 & 2, then 27 mg/m² once per day on days 8 & 9
  • Cycle 2 onwards: 27 mg/m² IV once per day on days 1, 2, 8, 9

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Chemotherapy

• Cisplatin (Platinol) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 160 mg/m²)

28- to 42-day cycles

References

1. Retrospective: Alsouqi A, Khan M, Dhakal B, Du L, Harrell S, Hari P, Cornell RF. KD-PACE Salvage Therapy for Aggressive Relapsed Refractory Multiple Myeloma, Plasma Cell Leukemia and Extramedullary Myeloma. Clin Lymphoma Myeloma Leuk. 2021 Aug;21(8):526-535. Epub 2021 Apr 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed

KRD-PACE

KRD-PACE: Kyprolis (Carfilzomib), Revlimid (Lenalidomide), Dexamethasone, Platinol (Cisplatin), Adriamycin (Doxorubicin), Cyclophosphamide, Etoposide

Regimen variant #1

Study	Dates of enrollment	Evidence
Cowan et al. 2020	2015-09 to 2019-02	Retrospective

Note: PACE was administered as a continuous infusion.

Targeted therapy

• Carfilzomib (Kyprolis) 20 mg/m² IV once per day on days 1, 2, 8, 9
• Lenalidomide (Revlimid) 10 to 25 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) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 160 mg/m²)

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

Regimen variant #2, modified

Study	Dates of enrollment	Evidence
Cowan et al. 2020	2015-09 to 2019-02	Retrospective

Note: PACE was administered as a continuous infusion.

Targeted therapy

• Carfilzomib (Kyprolis) 20 mg/m² IV once per day on days 1, 5, 6
• Lenalidomide (Revlimid) 10 to 25 mg PO once per day on days 5 to 8

Glucocorticoid therapy

• Dexamethasone (Decadron) 40 mg PO once per day on days 5 to 8

Chemotherapy

• Cisplatin (Platinol) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 5 (total dose per cycle: 40 mg/m²)
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 5 (total dose per cycle: 40 mg/m²)
• Cyclophosphamide (Cytoxan) 400 mg/m²/day IV continuous infusion over 96 hours, started on day 5 (total dose per cycle: 1600 mg/m²)
• Etoposide (Vepesid) 40 mg/m²/day IV continuous infusion over 96 hours, started on day 5 (total dose per cycle: 160 mg/m²)

Supportive therapy

• Filgrastim (Neupogen) 10 mcg/kg per day S.C. was begun on day 10. Note that this regimen was used to mobilize autologous peripheral blood stem cells in the context of this manuscript.
• Antiviral prophylaxis with Valacyclovir (Valtrex) daily (dose not specified)
• "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"
• All patients received anticoagulation therapy; individuals not receiving systemic therapeutic anticoagulation for another reason received enoxaparin 40 mg per day subcutaneously for DVT prophylaxis during chemotherapy

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

References

1. Retrospective: Cowan AJ, Green DJ, Karami M, Becker PS, Tuazon S, Coffey DG, Hyun TS, Libby EN, Gopal AK, Holmberg LA. KRD-PACE Mobilization for Multiple Myeloma Patients With Significant Residual Disease Before Autologous Stem-Cell Transplantation. Clin Lymphoma Myeloma Leuk. 2020 Sep;20(9):602-609. Epub 2020 Apr 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed

V-HyperCAD

V-HyperCAD: Velcade (Bortezomib), Hyperfractionated Cyclophosphamide, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Saraceni et al. 2017	2011-11 to 2015-09	Retrospective

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² SC once per day on days 1 & 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² IV every 12 hours on days 1 to 4 (total dose per cycle: 2400 mg/m²)
• 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

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 5 or 6
• Mesna (Mesnex) 350 mg/m²/day IV continuous infusion over 96 hours, started on day 1
• Antiviral prophylaxis with Acyclovir (Zovirax) daily (dose not specified)
• "Most patients also received antifungal, antibacterial, and Pneumocysitc jiroveci pneumonia prophylaxis"

Duration of each cycle not specified; for most patients, treatment cycles were administered every 4 weeks

References

1. Retrospective: Saraceni MM, Scott E, Maziarz RT, Siegel MB, Bassale S, Jiing S, Medvedova E. Modified hyperCVAD versus bortezomib-hyperCAD in patients with relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2018 Jan;18(1):e77-e84. Epub 2017 Nov 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed

VMPT

VMPT: Velcade (Bortezomib), Melphalan, Prednisone, Thalidomide

Regimen

Study	Dates of enrollment	Evidence
Palumbo et al. 2007	2004-2005	Phase 1/2

Note: This is the MTD dosing of this phase 1/2 trial.

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV bolus once per day on days 1, 4, 15, 22
• Thalidomide (Thalomid) 50 mg PO once per day on days 1 to 35

Chemotherapy

• Melphalan (Alkeran) 6 mg/m² PO once per day on days 1 to 5

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5

35-day cycle for 6 cycles

References

1. Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie Ematologicche dell'Adulto. Bortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma. Blood. 2007 Apr 1;109(7):2767-72. link to original article dosing details in abstract have been reviewed by our editors PubMed

Consolidation after second-line therapy

Bortezomib monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Richardson et al. 2005 (APEX)	2002-06 to 2003-10	Phase 3 (E-RT-switch-ooc)	High-dose dexamethasone	Seems to have superior OS1 (secondary endpoint) (HR 0.77) Superior TTP (primary endpoint) Median TTP: 6.22 vs 3.49 mo (HR 0.55)

¹Reported efficacy for APEX is based on the 2007 update.

Preceding treatment

• Bortezomib induction

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1, 8, 15, 22

Supportive therapy

• Bisphosphonate IV therapy once every 3 to 4 weeks unless contraindicated

35-day cycle for 3 cycles

References

1. APEX: Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00048230
   1. Pooled subgroup analysis: Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM, Anderson KC. Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2007 Jan;21(1):151-7. Epub 2006 Nov 9. link to original article PubMed
   2. Update: Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San Miguel J, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007 Nov 15;110(10):3557-60. Epub 2007 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed

ITd

ITd: Ixazomib, Thalidomide, low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cook et al. 2024 (ACCoRD)	2017-12-12 to 2023-04-21	Phase 3 (E-esc)	Observation	Superior PFS (primary endpoint) Median PFS: 20 vs 13 mo (HR 0.55, 95% CI 0.39-0.78)

Preceding treatment

• Salvage autologous HSCT

Targeted therapy

• Ixazomib (Ninlaro) 4 mg PO once per day on days 1, 8, 15
• Thalidomide (Thalomid) as follows:
  • Cycles 1 & 2: 100 mg PO once per day on days 1 to 28

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 2: 40 mg PO once per day on days 1, 8, 15, 22

28-day cycles

References

1. ACCoRD: Cook G, Ashcroft AJ, Senior E, Olivier C, Hockaday A, Richards J, Cavenagh JD, Snowden JA, Drayson MT, de Tute R, Roberts L, Owen RG, Yong K, Garg M, Boyd K, Sati H, Gillson S, Cook M, Cairns DA, Parrish C; United Kingdom Myeloma Research Alliance. Ixazomib as consolidation and maintenance versus observation in patients with relapsed multiple myeloma eligible for salvage autologous stem-cell transplantation (Myeloma XII [ACCoRD]): interim analysis of a multicentre, open-label, randomised, phase 3 trial. Lancet Haematol. 2024 Nov;11(11):e816-e829. Epub 2024 Sep 6. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN10038996

Melphalan monotherapy, then auto HSCT

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cook et al. 2014 (NCRI Myeloma X Relapse)	2008-2012	Phase 3 (E-esc)	Cyclophosphamide	Seems to have superior OS1 (secondary endpoint) (HR 0.56, 95% CI 0.35-0.90) Superior TTP (primary endpoint) Median TTP: 19 vs 11 mo (HR 0.36, 95% CI 0.25-0.53)

¹Reported efficacy is based on the 2016 update.

Preceding treatment

• Salvage PAD x 4

Chemotherapy

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

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

1. NCRI Myeloma X Relapse: Cook G, Williams C, Brown JM, Cairns DA, Cavenagh J, Snowden JA, Ashcroft AJ, Fletcher M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Chalmers A, O'Connor S, Drayson MT, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. High-dose chemotherapy plus autologous stem-cell transplantation as consolidation therapy in patients with relapsed multiple myeloma after previous autologous stem-cell transplantation (NCRI Myeloma X Relapse [Intensive trial]): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Jul;15(8):874-85. Epub 2014 Jun 16. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Dosage error in article text. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00747877
   1. Update: Cook G, Ashcroft AJ, Cairns DA, Williams CD, Brown JM, Cavenagh JD, Snowden JA, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Chown S, Heartin E, O'Connor S, Drayson MT, Hockaday A, Morris TC; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The effect of salvage autologous stem-cell transplantation on overall survival in patients with relapsed multiple myeloma (final results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Lancet Haematol. 2016 Jul;3(7):e340-51. link to original article PubMed
   2. Subgroup analysis: Cook G, Royle KL, O'Connor S, Cairns DA, Ashcroft AJ, Williams CD, Hockaday A, Cavenagh JD, Snowden JA, Ademokun D, Tholouli E, Andrews VE, Jenner M, Parrish C, Yong K, Cavet J, Hunter H, Bird JM, Pratt G, Drayson MT, Brown JM, Morris TCM; National Cancer Research Institute Haemato-oncology Clinical Studies Group. The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial. Br J Haematol. 2019 May;185(3):450-467. Epub 2019 Feb 6. link to original article link to PMC article PubMed

Maintenance after second-line therapy

Bortezomib & Cyclophosphamide

Regimen

Study	Dates of enrollment	Evidence
de Waal et al. 2015	2009-2013	Phase 2

Preceding treatment

• Salvage VDC x 6

Targeted therapy

• Bortezomib (Velcade) 1.3 mg/m² IV or SC once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day

Supportive therapy

• Pneumococccal and anti-fungal prophylaxis "according to local protocols"
• Valacyclovir (Valtrex) (dose not specified) for herpes prophylaxis

14-day cycle for up to 26 cycles (1 year)

References

1. de Waal EG, de Munck L, Hoogendoorn M, Woolthuis G, van der Velden A, Tromp Y, Vellenga E, Hovenga S. Combination therapy with bortezomib, continuous low-dose cyclophosphamide and dexamethasone followed by one year of maintenance treatment for relapsed multiple myeloma patients. Br J Haematol. 2015 Dec;171(5):720-5. Epub 2015 Sep 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed

KPD

KPD: Kyprolis (Carfilzomib), Pomalidomide, Dexamethasone
CPD: Carfilzomib, Pomalidomide, Dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Shah et al. 2015 (PO-MM-PI-0034)	2011 to not reported	Phase 1

Note, although this is described as a Phase 1 trial, an additional 20 patients were enrolled at the MTD, which is the dose reported here.

Preceding treatment

• Salvage KPD x 6

Targeted therapy

• Carfilzomib (Kyprolis) 27 mg/m² IV over 30 minutes once per day on days 1, 2, 15, 16
• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Glucocorticoid therapy

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

Supportive therapy

• "Anti-viral therapy"
• Aspirin 81 mg PO once per day
  • Low molecular weight heparin was used in patients intolerant of aspirin

28-day cycles

References

1. PO-MM-PI-0034: Shah JJ, Stadtmauer EA, Abonour R, Cohen AD, Bensinger WI, Gasparetto C, Kaufman JL, Lentzsch S, Vogl DT, Gomes CL, Pascucci N, Smith DD, Orlowski RZ, Durie BG. Carfilzomib, pomalidomide, and dexamethasone for relapsed or refractory myeloma. Blood. 2015 Nov 12;126(20):2284-90. Epub 2015 Sep 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01464034

Pomalidomide monotherapy

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Paludo et al. 2017 (MC1082)	2012-2014	Phase 1/2	ORR: 86%

Preceding treatment

• Salvage PVD x 8

Targeted therapy

• Pomalidomide (Pomalyst) 4 mg PO once per day on days 1 to 21

Supportive therapy

• Aspirin 325 mg PO once per day
  • Full dose anticoagulation with LMWH or Warfarin (Coumadin) could be substituted at physician discretion
• Acyclovir (Zovirax) or equivalent for VZV prophylaxis

28-day cycles

References

1. MC1082: Paludo J, Mikhael JR, LaPlant BR, Halvorson AE, Kumar S, Gertz MA, Hayman SR, Buadi FK, Dispenzieri A, Lust JA, Kapoor P, Leung N, Russell SJ, Dingli D, Go RS, Lin Y, Gonsalves WI, Fonseca R, Bergsagel PL, Roy V, Sher T, Chanan-Khan AA, Ailawadhi S, Stewart AK, Reeder CB, Richardson PG, Rajkumar SV, Lacy MQ. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed lenalidomide-refractory multiple myeloma. Blood. 2017 Sep 7;130(10):1198-1204. Epub 2017 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT01212952

Pomalidomide & Prednisone

Regimen

Study	Dates of enrollment	Evidence	Efficacy
Larocca et al. 2013 (PO0023)	2010-2012	Phase 1/2	ORR: 51%

Details are for the phase 2 portion of the published phase 1/2 trial.

Preceding treatment

• Salvage PCP x 6

Targeted therapy

• Pomalidomide (Pomalyst) 1 mg PO once per day

Glucocorticoid therapy

• Prednisone (Sterapred) 25 mg PO once every other day

Supportive therapy

• Aspirin 100 mg PO once per day or low-molecular-weight heparin "according to patient risk"

Continued indefinitely

References

1. PO0023: Larocca A, Montefusco V, Bringhen S, Rossi D, Crippa C, Mina R, Galli M, Marcatti M, La Verde G, Giuliani N, Magarotto V, Guglielmelli T, Rota-Scalabrini D, Omedé P, Santagostino A, Baldi I, Carella AM, Boccadoro M, Corradini P, Palumbo A. Pomalidomide, cyclophosphamide and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open label study. Blood. 2013 Oct 17;122(16):2799-806. Epub 2013 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01166113

RVD

RVD: Revlimid (Lenalidomide), Velcade (Bortezomib), Dexamethasone
VDR: Velcade (Bortezomib), Dexamethasone, Revlimid (Lenalidomide)
VRD: Velcade (Bortezomib), Revlimid (Lenalidomide), Dexamethasone
VRd: Velcade (Bortezomib), Revlimid (Lenalidomide), low-dose dexamethasone

Regimen

Study	Dates of enrollment	Evidence
Richardson et al. 2014 (DFCI 06-147)	2006-2008	Phase 2

Preceding treatment

• RVD salvage

Targeted therapy

• Lenalidomide (Revlimid) (at previously tolerated dose) PO once per day on days 1 to 14
• Bortezomib (Velcade) (at previously tolerated dose) IV once per day on days 1 & 8

Glucocorticoid therapy

• Dexamethasone (Decadron) 10 mg PO once per day on days 1, 2, 8, 9

Supportive therapy

• Aspirin 81 mg or 325 mg PO once per day
• Antiviral therapy for VZV prophylaxis

21-day cycles

References

1. DFCI 06-147: Richardson PG, Xie W, Jagannath S, Jakubowiak A, Lonial S, Raje NS, Alsina M, Ghobrial IM, Schlossman RL, Munshi NC, Mazumder A, Vesole DH, Kaufman JL, Colson K, McKenney M, Lunde LE, Feather J, Maglio ME, Warren D, Francis D, Hideshima T, Knight R, Esseltine DL, Mitsiades CS, Weller E, Anderson KC. A phase II trial of lenalidomide, bortezomib and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014 Mar 6;123(10):1461-9. Epub 2014 Jan 15. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00378209

Response criteria

• IMWG international uniform response criteria for multiple myeloma. (Durie et al. Leukemia 2006) PubMed
  • Make note of these errors which remain in the online version of the IMWG criteria as of 7/7/2013.
  • Clarification of the definition of complete response in multiple myeloma (Leukemia 2015) PubMed
• European Blood and Marrow Transplant (EBMT) criteria. (Bladé et al. Br J Hematol 1998) PubMed

Prognosis

Durie-Salmon Staging System - 1975

Composed of four factors with a modifier based on renal function

• Serum levels of monoclonal protein (only defined for IgM, IgA, and Bence-Jones)
• Number of lytic bone lesions
• Hemoglobin
• Serum calcium level

Risk stratification

• Stage I: (must meet ALL criteria)
  • Hemoglobin greater than 10 g/dL
  • Calcium normal or less than or equal to 12 mg/dL
  • Skeletal survey with normal bone structure (scale 0) or solitary bone plasmacytoma only
  • Monoclonal protein relatively small (IgG M-spike value less than 5 g/dL OR IgA M-spike value less than 3 g/dL OR urine light chain protein less than 4 g/24 hr)
• Stage II: not stage I or stage III
• Stage III: (if meets ANY of the criteria)
  • Hemoglobin less than 8.5 g/dL
  • Calcium greater than 12 mg/dL
  • Skeletal survey with extensive skeletal destruction and major fractures
  • Monoclonal protein relatively large (IgG M-spike value greater than 7 g/dL OR IgA M-spike value greater than 5 g/dL OR urine light chain protein greater than 12 g/24 hr)

Modifier

• A: relatively normal creatinine (less than 2 mg/dL)
• B: creatinine greater than or equal to 2 mg/dL

References

1. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975 Sep;36(3):842-54. link to original article PubMed

International Staging System (ISS) - 2005

Composed of two factors

• Serum albumin level
• Serum beta-2 microglobulin level

Risk stratification

• Stage I: Median survival of 62 months
  • Beta-2 microglobulin less than 3.5 mg/l
  • Albumin greater than or equal to 3.5 g/dl
• Stage II: Median survival of 44 months
  • Not meeting stage I or stage III criteria
• Stage III: Median survival of 29 months
  • Beta-2 microglobulin greater than or equal to 5.5 mg/l

References

1. Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J. International staging system for multiple myeloma. J Clin Oncol. 2005 May 20;23(15):3412-20. Epub 2005 Apr 4. link to original article PubMed
2. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009 Jan;23(1):3-9. Epub 2008 Oct 30. link to original article link to PMC article PubMed

IMWG consensus on risk stratification - 2013

Composed of four factors

• Serum albumin level
• Serum beta-2 microglobulin level
• Age
• Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)

Risk stratification

• Low risk: (must meet all criteria) Median survival of greater than 10 years
  • ISS Stage I or II
  • Age less than 55 years
  • Absence of the following: del(17p13), t(4;14), +1q21
• Standard risk: Median survival of 7 years
  • Not meeting low risk or high risk criteria
• High risk: (if meets both criteria) Median survival of 2 years
  • ISS Stage II or III
  • Either of the following: del(17p13) or t(4;14)

References

1. Chng WJ, Dispenzieri A, Chim CS, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, San Miguel J, Sonneveld P, Cavo M, Usmani S, Durie BG, Avet-Loiseau H; International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014 Feb;28(2):269-77. Epub 2013 Aug 26. link to original article PubMed

Revised International Staging System (R-ISS) - 2015

Composed of four factors

• Serum albumin level
• Serum beta-2 microglobulin level
• Serum LDH
• Chromosomal abnormalities detected by interphase fluorescent in situ hybridization (FISH)

Risk stratification

• Low risk: 5-year overall survival = 82%
  • Beta-2 microglobulin less than 3.5 mg/l
  • Albumin less than or equal to 3.5 g/dl
  • LDH less than the upper limit of normal range
  • Absence of the following: del(17p), t(4;14), t(14;16)
• Intermediate risk: 5-year overall survival = 62%
  • Not meeting low risk or high risk criteria
• High risk: (if meets ANY of the criteria) 5-year overall survival = 40%
  • Beta-2 microglobulin greater than or equal to 5.5 mg/l
  • LDH greater than the upper limit of normal range
  • Any of the following: del(17p), t(4;14), t(14;16)

References

1. Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised International Staging System for multiple myeloma: a report from International Myeloma Working Group. J Clin Oncol. 2015 Sep 10;33(26):2863-9. Epub 2015 Aug 3. link to original article link to PMC article PubMed

Second Revised International Staging System (R2-ISS) - 2022

Composed of four factors

• ISS-III: 1.5 points
• ISS-II: 1 point
• del(17p): 1 point
• High LDH: 1 point
• t(4;14): 1 point
• 1q+: 0.5 points

Risk stratification

• Low risk: 0 points
  • Median OS: NYR
  • Median PFS: 68 mo
• Low-intermediate risk: 0.5 to 1 points
  • Median OS: 109.2 mo
  • Median PFS: 45.5 mo
• Intermediate-high risk: 1.5 to 2.5 points
  • Median OS: 68.5 mo
  • Median PFS: 30.2 mo
• High risk: 3 to 5 points
  • Median OS: 37.9 mo
  • Median PFS: 19.9 mo

References

1. D'Agostino M, Cairns DA, Lahuerta JJ, Wester R, Bertsch U, Waage A, Zamagni E, Mateos MV, Dall'Olio D, van de Donk NWCJ, Jackson G, Rocchi S, Salwender H, Bladé Creixenti J, van der Holt B, Castellani G, Bonello F, Capra A, Mai EK, Dürig J, Gay F, Zweegman S, Cavo M, Kaiser MF, Goldschmidt H, Hernández Rivas JM, Larocca A, Cook G, San-Miguel JF, Boccadoro M, Sonneveld P. Second Revision of the International Staging System (R2-ISS) for Overall Survival in Multiple Myeloma: A European Myeloma Network (EMN) Report Within the HARMONY Project. J Clin Oncol. 2022 Oct 10;40(29):3406-3418. Epub 2022 May 23. Erratum in: J Clin Oncol. 2022 Dec 1;40(34):4032. link to original article PubMed

Miscellaneous

1. Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C, Leyvraz S, Michallet M, Yakoub-Agha I, Garderet L, Marit G, Michaux L, Voillat L, Renaud M, Grosbois B, Guillerm G, Benboubker L, Monconduit M, Thieblemont C, Casassus P, Caillot D, Stoppa AM, Sotto JJ, Wetterwald M, Dumontet C, Fuzibet JG, Azais I, Dorvaux V, Zandecki M, Bataille R, Minvielle S, Harousseau JL, Facon T, Mathiot C. Genetic abnormalities and survival in multiple myeloma: the experience of the Intergroupe Francophone du Myélome. Blood. 2007 Apr 15;109(8):3489-95. Epub 2007 Jan 5. link to original article PubMed
2. Avet-Loiseau H, Hulin C, Campion L, Rodon P, Marit G, Attal M, Royer B, Dib M, Voillat L, Bouscary D, Caillot D, Wetterwald M, Pegourie B, Lepeu G, Corront B, Karlin L, Stoppa AM, Fuzibet JG, Delbrel X, Guilhot F, Kolb B, Decaux O, Lamy T, Garderet L, Allangba O, Lifermann F, Anglaret B, Moreau P, Harousseau JL, Facon T. Chromosomal abnormalities are major prognostic factors in elderly patients with multiple myeloma: the Intergroupe Francophone du Myélome experience. J Clin Oncol. 2013 Aug 1;31(22):2806-9. Epub 2013 Jun 24. link to original article link to PMC article PubMed

External links

• Mayo Clinic mSMART (Stratification for Myeloma And Risk-adapted Therapy)