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Management of relapsed/refractory multiple myeloma (RRMM)

Relapses in MM are almost inevitable. The treatment of relapsed patients requires an individualized approach that can be influenced by many factors, including: prior therapy, patient preference, fitness and comorbidities.1

There are three main treatment options for RRMM: re-treating with a previously used agent, switching to a different agent within the same drug class, or switching to a different class.1

The response to previous treatments should also be considered. For patients who demonstrate disease progression while on therapy, or who had only a limited response, switching to a different drug class may be considered. Alternatively, it may be possible to use a second-generation agent in the same drug class as the treatment used at first line. In general, triplet regimens are recommended for treatment until disease progression, except in extremely frail patients.3

Several new agents have been introduced that can improve outcomes for RRMM patients in clinical practice. These include second-generation proteasome inhibitors and immunomodulatory agents, anti-CD38 and SLAMF7 antibodies, B-cell maturation antigen (BCMA)-directed antibody-drug conjugates, XPO1-inhibitors, and CAR-T cell therapy. Future developments are also looking at emerging treatments with different mechanisms of action. Bispecific T-cell engagers (BiTE) allow for engagement of T cells with tumor cells, resulting in formation of cytolytic synapses and tumor cell lysis. Ongoing research is assessing mechanisms of resistance to CAR-T, using combination immune approaches with CAR-T, and using CAR-T earlier in the disease course in order to achieve more durable responses.2,3

Considering the number of new therapies now available, it should be possible for patients to receive treatment at relapse with an agent to which they may not be resistant. However, there are limited long-term real-world effectiveness data for these new agents following different initial treatment combinations.

Conclusion

The RRMM treatment landscape has grown significantly over the past decade, with a number of treatment options now available. The availability of new agents makes combinations of drugs from different classes possible, and the latest findings from clinical trials indicate that the benefits may outweigh the risk of patients developing multidrug resistance. Real-world evidence is key to advancing our understanding of the effectiveness that can be achieved when MM treatments are prescribed to a broader population of patients than those who are enrolled in RCTs.

References

1. Goldschmidt H et al. Ann Hematol. 2019;98(1):1-18. 2. Gulla A, Anderson KC. Haematologica 2020;105(10):2358-2367. 3. Nathwani N, Bertamini L, Banerjee R, et al. When and how to treat relapsed multiple myeloma. Am Soc Clin Oncol Educ Book 2021 Mar;41:358-375.

Abbreviations

BCMA, B-cell maturation antigen; BiTE, bispecific T-cell engagers; CAR-T, Chimeric Antigen Receptors Cell Therapy; CD38, cluster of differentiation 38; MM, multiple myeloma; RCT, randomized controlled trial; RRMM, relapsed/refractory multiple myeloma; SLAMF7, signalling lymphocytic activation molecule family 7; XPO1, Exportin 1.