Gaps and opportunities in the treatment of relapsed-refractory multiple myeloma: Consensus recommendations of the NCI Multiple Myeloma Steering Committee

Abstract

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.

Defining drug/drug class refractoriness vs lines of therapy in relapsed/refractory multiple myeloma

“…[ 1 ]; which are more dependent on practice patterns than disease biology. The increasing number of treatment options and different permutations and combinations of drugs makes it difficult to understand the actual significance of the number of prior lines received, owing to variability in what constitutes a line [ 11 ]. We hypothesized that a more meaningful and reliable way would be to define prior therapy by the number of drugs or the number of drug classes that a patient is refractory to, which could better reflect the disease biology.…”

Iopofosine I-131 treatment in late-line patients with relapsed/refractory multiple myeloma post anti-BCMA immunotherapy

“…The disease is characterized by the uncontrolled expansion of malignant plasma cells in the bone marrow, resulting in aberrantly high levels of monoclonal immunoglobulins that can be detected in the blood, urine, or both. Although effective pharmacologic therapy and autologous hematopoietic stem cell transplantation have improved patient response rates and progression-free survival (PFS) [ 1 , 2 ], the prognosis for patients with multi-drug refractory MM remains poor [ 2 , 3 ]. B-cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 ( TNFRSF17 ), is highly expressed by plasma cells, and can be effectively targeted via chimeric antigen receptor (CAR) T cells [ 4 ].…”

“…Several BCMA-directed therapies have been approved or are in clinical development, including CAR T-cell therapies, bispecific antibodies, and antibody drug conjugates [ 2 ]. CAR T therapy studies have shown a high number of patients achieving response; however, several challenges make this option unsuitable for R/RMM patients who are unfit for the conditioning regimens or who have inadequate disease control [ 4 , 14 ].…”

“…Although the response rates for the CAR Ts range from 70 to >90%, high relapse rates (50%) within the first 12 months continue to pose clinical challenges. Additionally, tolerability remains a concern with high rates of cytokine release syndrome and neurotoxicity [ 2 ]. Another anti-BCMA immunotherapy alternative, belantamab mafodotin (an anti-BCMA antibody drug conjugate using the microtubule-targeting cytotoxin monomethyl auristatin-F), was recently approved by the FDA for treatment of R/RMM patients who have received ≥4 prior therapies (including anti-CD38 antibodies, PIs, and IMiDs) [ 2 ].…”

“…Additionally, tolerability remains a concern with high rates of cytokine release syndrome and neurotoxicity [ 2 ]. Another anti-BCMA immunotherapy alternative, belantamab mafodotin (an anti-BCMA antibody drug conjugate using the microtubule-targeting cytotoxin monomethyl auristatin-F), was recently approved by the FDA for treatment of R/RMM patients who have received ≥4 prior therapies (including anti-CD38 antibodies, PIs, and IMiDs) [ 2 ]. Similar to the CAR T therapies, early relapse and resistance to belantamab remain a challenge, leaving post anti-BCMA an area of unmet need in MM [ 8 ].…”