Numerous Regimens Proposed for Relapsed or Refractory Myeloma

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Although patients with multiple myeloma can respond to initial treatment, once a patient has had three or four different types of therapy, and the disease is deemed relapsed or refractory, treatment becomes more complicated. This is related to both clinical characteristics, as patients may develop lower blood cell counts and other complications, as well as acquired resistance to numerous drug classes. Early relapse is considered more treatable than late relapse, and the prognosis for patients with “triple-class refractory” disease is poor.

“For patients who have received one to three prior types of treatment, the introduction of a monoclonal antibody should be a strong consideration if they have not previously received one.”
— Natalie S. Callander, MD

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“Despite advances in therapy, relapse is essentially inevitable in multiple myeloma,” said Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, who discussed the management of relapsed or refractory multiple myeloma during the 2021 National Comprehensive Cancer Network (NCCN) Virtual Congress: Hematologic Malignancies.1

“The presentation of relapsed multiple myeloma varies,” she noted, and disease progression can be defined in two different ways: by laboratory parameters or by a new clinical event. “These two groups require different approaches involving … reevaluation and review. For patients who have received one to three prior types of treatment, the introduction of a monoclonal antibody should be a strong consideration if they have not previously received one,” she stated.

As background, the current treatment paradigm for newly diagnosed multiple myeloma in transplant-eligible patients includes induction therapy with three or four drugs (eg, bortezomib/lenalidomide/dexamethasone with or without daratumumab, bortezomib/thalidomide/dexamethasone, bortezomib/cyclophosphamide/dexamethasone with or without daratumumab) and consolidation with one or two autologous stem cell transplants, followed by maintenance therapy with lenalidomide, bortezomib, ixazomib, or daratumumab. Transplant-ineligible patients with newly diagnosed myeloma are treated with induction therapy followed by continuous therapy. With these regimens, disease control has improved, and median progression-free survival is often 3 to 5 years.

Once patients relapse or the disease is deemed refractory, the list of potential regimens is long and complex.

Early Relapse

U.S. Food and Drug Administration (FDA)-approved triplets for early relapse of multiple myeloma include:

  • daratumumab/lenalidomide/dexamethasone
  • pomalidomide/elotuzumab/dexamethasone
  • isatuximab/pomalidomide/dexamethasone
  • daratumumab/carfilzomib/dexamethasone
  • isatuximab/carfilzomib/dexamethasone.

Dr. Callander noted that subcutaneous daratumumab/pomalidomide/dexamethasone is one of the most frequently selected regimens at first relapse, based on phase III data from the APOLLO trial. In that study, median progression-free survival with daratumumab/pomalidomide/dexamethasone was 12.4 months vs 6.9 months with pomalidomide and dexamethasone—a 27% improvement (P = .0018).2

The triplet of daratumumab/carfilzomib/dexamethasone was studied in the CANDOR trial. Median progression-free survival was not reached in the triplet arm vs 15.8 months in patients receiving carfilzomib plus dexamethasone (P = .0027).3

The IKEMA study compared isatuximab plus carfilzomib/dexamethasone vs the carfilzomib dexamethasone doublet in 302 patients with relapsed or refractory myeloma treated with one to three prior lines of therapy (but not carfilzomib).4 That three-drug combination led to a more than doubling of the measurable residual disease (MRD)-negative rate in patients with at least a very good partial response. In the intent-to-treat population, the MRD-negative rate was approximately 30%.

The combination of elotuzumab, pomalidomide, and dexamethasone was compared with pomalidomide plus dexamethasone in 111 patients; use of the triplet led to a 46% reduction in the risk of disease progression or death.5 Median progression-free survival was 10.3 months vs 4.7 months, respectively (P = .0078). The regimen is now approved by the FDA for relapsed or refractory myeloma.5

Several combinations are used in patients with early-relapse myeloma who have been exposed to or are refractory to antibody therapy. Combinations supported by phase III data include:

  • pomalidomide/bortezomib/dexamethasone
  • selinexor/bortezomib/dexamethasone
  • bortezomib/panobinostat/dexamethasone
  • lenalidomide/carfilzomib/dexamethasone.

Other triplets used in this setting include pomalidomide/carfilzomib/dexamethasone, lenalidomide/cyclophosphamide/dexamethasone, and carfilzomib/cyclophosphamide/dexamethasone.

Dr. Callander pointed out that oral triplet regimens are especially useful to limit in-person visits. All-oral triplets with phase III data include the combination of ixazomib, pomalidomide, and dexamethasone. Phase I and II data support the use of ixazomib, lenalidomide, and dexamethasone; ixazomib, cyclophosphamide, and dexamethasone; cyclophosphamide, pomalidomide, and prednisone; and selinexor, pomalidomide, and dexamethasone as other reasonable choices for all-oral triplets that could be employed at relapse.

Late Relapse

Treatment selection for patients who relapse after three prior regimens is based in part on an assessment of the patient’s fitness and stability. There may be a clinical trial available. For patients who have not undergone transplant, autologous peripheral blood stem cell transplant should be considered. The addition of an alkylating agent may be another option, Dr. Callander advised.

“Survival of [patients with] triple-class refractory multiple myeloma is poor,” she said.

Suggested regimens for patients who have received at least four prior therapies including an anti-CD18 antibody, a proteasome inhibitor, and an immunomodulatory drug, include belantamab mafodotin-blmf and idecabtagene vicleucel. For patients with a late relapse whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory drugs, and an anti-CD38 antibody, selinexor plus dexamethasone is recommended.

“With selinexor, supportive care and dosing are important. Weekly dosing is preferable, as are lower doses. Support with fluids, antiemetics, and nutrition as needed.”
— Natalie S. Callander, MD

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“With selinexor, supportive care and dosing are important. Weekly dosing is preferable, as are lower doses. Attention to fluid intake, judicious use of antiemetics and keeping an eye on nutrition help patients better tolerate selinexor. Combinations with selinexor look promising in late relapse patients,” she stated.

Belantamab mafodotin is an off-the-shelf anti–B-cell maturation antigen (BCMA) therapy specific to multiple myeloma. In a single-arm study, the overall response rate in late relapse was 31%.6 The most common adverse event was keratopathy. “Coming soon are combinations with belantamab mafodotin that include pomalidomide and bortezomib,” she noted.

The KARMMA trial evaluated the anti-BCMA chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel in patients with relapsed or refractory multiple myeloma. Updated data showed that the best response was 100% at the highest dose. The overall best response rate at all dose levels was 75.8%.8 With longer-follow-up, no new safety signals have emerged.

The CARTITUDE-1 phase Ib/II trial evaluated ciltacabtagene autoleucel, another CAR T-cell therapy, in this setting.9 Almost all patients (27 of 29) developed cytokine-release syndrome, which was grade 3 or higher in 7%. One death was attributed to the reaction. With 18 months of follow-up, the overall response rate was 97.9%, progression-free survival was 66%, and overall survival was 81%.

Idecabtagene vicleucel is indicated for patients with myeloma who have received at least four lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. Limitations to this therapy include manufacturing time and accessibility, she noted.

Several bispecific T-cell engagers are under study for relapsed multiple myeloma, including four BCMA-targeted agents. Selected myeloma CAR T-cell therapies include idecabtagene vicleucel, ciltacabtagene autoleucel, P-BCMA-101, and bb21217. These agents have response rates ranging from 57% to 98% and yield an overall survival approaching 2 years. They carry a high risk of cytokine-release syndrome and a 3.8% to 18% risk of immune effector cell–associated neurotoxicity syndrome.


There are many treatment choices available for early relapse of multiple myeloma (defined as disease progression after one to three prior treatments). Options include adding a monoclonal antibody to treatment, using a different proteasome inhibitor or immunomodulatory agent, enrolling the patient in a clinical trial, and referring to transplant, if appropriate.

For late relapse (more than four prior treatments), the first choice would be a clinical trial, if possible. These patients can receive selinexor combinations, belantamab mafodotin, idecabtagene vicleucel, ciltacabtagene autoleucel (once approved, which is likely to be soon), alkylators, and salvage autologous transplant. 

DISCLOSURE: Dr. Callander reported no conflicts of interest.


1. Callander N: Maneuvering the complex web of treatment options for relapsed/refractory multiple myeloma. 2021 NCCN Virtual Congress: Hematologic Malignancies. Presented October 15, 2021.

2. Dimopoulos MA, Terpos E, Boccadoro M, et al: 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 22:801-812, 2021.

3. Dimopoulos MA, Quach H, Mateos MV, et al: Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): Results from a randomized, multicenter, open-label, phase 3 study. Lancet 396:186-197, 2020.

4. Moreau P, Dimopoulos MA, Mikhael J, et al: Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): A multicenter, open-label, randomised phase 3 trial. Lancet 22:2361-2371, 2021.

5. Dimopoulos MA, Dytfeld D, Grosicki S, et al: Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med 379:1811-1822, 2018.

6. Lonial S, Lee HC, Badros A, et al: Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): A two-arm, randomised, open-label, phase 2 study. Lancet Oncol 21:207-221, 2020.

7. Haney S, Flanagan K, Varney M, et al: Melflufen rapidly accumulates within tumor cells and distributes as an alkylating payload to the nucleus and mitochondria. 2021 European Hematology Association Virtual Congress. Poster EP945.

8. Munshi N, Anderson LD, Shah N, et al: Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 384:705-716, 2021.

9. Madduri D, Usmani SZ, Jagannath S, et al: Results from CARTITUDE-1: A phase 1b/2 study of JNJ-4528, a CAR-T therapy directed against B-cell maturation antigen in patients with relapsed and/or refractory multiple myeloma. Blood 134(suppl 1):577, 2019.