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CAR T cell therapies for patients with multiple myeloma

Nature Reviews Clinical Oncology volume 18, pages 71–84 (2021)Cite this article

Subjects

Abstract

Despite several therapeutic advances over the past decade, multiple myeloma (MM) remains largely incurable, indicating a need for new treatment approaches. Chimeric antigen receptor (CAR) T cell therapy works by mechanisms distinct from those of other MM therapies and involves the modification of patient or donor T cells to target specific cell-surface antigens. B cell maturation antigen (BCMA) is expressed only on plasma cells, a small subset of B cells and MM cells, which makes it a suitable target antigen for such therapies. At the time of writing, data from >20 clinical trials involving anti-BCMA CAR T cells have demonstrated that patients with relapsed and/or refractory MM can achieve objective responses. These early investigations have been instrumental in demonstrating short-term safety and efficacy; however, most patients do not have disease remission lasting >18 months. Attempts to reduce or delay the onset of relapsed disease are underway and include identifying additional CAR T cell target antigens and methods of enhancing BCMA expression on MM cells. Engineering CAR T cells to enhance both the activity and safety of treatment continues to be a promising avenue for improvement. In this Review we summarize data from clinical trials that have been carried out to date, describe novel antigens that could be targeted in the future, and highlight potential future innovations that could enhance the efficacy and/or reduce the toxicities associated with CAR T cell therapies.

Key points

  • New treatments for relapsed and/or refractory multiple myeloma (MM) are needed. Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have demonstrated efficacy in patients with heavily pretreated MM with deep remission in a subset of patients.

  • Results from the many clinical trials testing anti-BCMA CAR T cells will help guide the development of the next generation of CAR T cell therapies for patients with MM.

  • The phenotypic heterogeneity of MM poses a major barrier to achieving durable, relapse-free responses with CAR T cells and necessitates improvements in the current approaches.

  • Targeting new antigens, either alone or in combination with BCMA, or using pharmacological agents to increase target antigen density on MM cells might reduce the risk of MM relapse following treatment with CAR T cells.

  • Optimizing CAR designs by modifying the antigen-binding, co-stimulatory, hinge and/or transmembrane domains might improve clinical outcomes. Including a genetically encoded suicide switch might improve the overall safety of CAR T cell therapy.

  • Substitution of standard lymphodepleting chemotherapy regimens with drugs that have greater activity against MM or adding maintenance therapy after CAR T cell infusion might result in more durable and/or deeper responses.

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Fig. 1: Heterogeneity and resistance of MM subclones.
Fig. 2: Structure of a CAR.
Fig. 3: Structure of CARs and CAR-expressing T cells.

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  1. Surgery Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA

    Lekha Mikkilineni & James N. Kochenderfer

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Mikkilineni, L., Kochenderfer, J.N. CAR T cell therapies for patients with multiple myeloma. Nat Rev Clin Oncol 18, 71–84 (2021). https://doi.org/10.1038/s41571-020-0427-6

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