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  • Review Article
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Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins

Abstract

A better understanding of the roles of the adaptive and innate immune systems in the oncogenesis of cancers including multiple myeloma (MM) has led to the development of novel immune-based therapies. B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D) and Fc receptor-like protein 5 (FcRL5, also known as FcRH5) are cell-surface transmembrane proteins expressed by plasma cells, and have been identified as prominent immunotherapeutic targets in MM, with promising activity demonstrated in patients with heavily pretreated relapsed and/or refractory disease. Indeed, since 2020, antibody–drug conjugates, bispecific T cell engagers and autologous chimeric antigen receptor T cells targeting BCMA or GPRC5D have been approved for the treatment of relapsed and/or refractory MM. However, responses to these therapies are not universal, and acquired resistance invariably occurs. In this Review, we discuss the various immunotherapeutic approaches targeting BCMA, GPRC5D and FcRL5 that are currently either available or in clinical development for patients with MM. We also review the mechanisms underlying resistance to such therapies, and discuss potential strategies to overcome these mechanisms and improve patient outcomes.

Key points

  • Novel targeted immunotherapies including antibody–drug conjugates (ADCs), chimeric antigen receptor (CAR) T cells and bispecific T cell engagers (BTEs) have revolutionized the treatment of multiple myeloma (MM).

  • These agents have been developed to target B cell maturation antigen, G protein-coupled receptor family C group 5 member D and Fc receptor-like protein 5, which are cell-surface transmembrane proteins expressed by the malignant plasma cells, and have shown unprecedented efficacy in patients with heavily pretreated relapsed and/or refractory disease.

  • ADCs, BTEs and CAR T cells targeting these antigens are associated with unique and sometimes severe toxicities. Therefore, careful management and mitigation strategies are required to improve patient outcomes.

  • The effectiveness of these agents is limited by various mechanisms of resistance reflecting the adaptive nature of MM cells and their capacity to exploit the dysregulated immune system associated with this disease. These mechanisms include cancer cell-intrinsic, T cell-related and tumour microenvironment-related factors.

  • Dynamic surveillance for antigen escape and functional evaluation of T cell fitness is required to optimize the sequencing of these immunotherapies and improve patient outcomes.

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Fig. 1: Mechanisms of action of novel targeted immunotherapies in MM.
Fig. 2: Mechanisms of resistance to novel targeted immunotherapies for MM.

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Acknowledgements

A.G. acknowledges research support from Start-UP grant from the Italian Association for Cancer Research (project number 27750); a FPRC “5xmille” 2019 Ministry of Health project (IDEE); and a FPRC “5xmille” 2021 Ministry of Health project (EMAGEN-FaBer).

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P.N. reports honoraria from Bristol Myers Squibb (BMS), Janssen, Pfizer and Sanofi, and is a consultant/advisory board member for BMS and Janssen. N.J.B. reports honoraria from Amgen, BMS, Janssen, Pfizer and Sanofi, and is a consultant/advisory board member for BMS, Janssen and Pfizer. K.C.A. is a consultant/advisory board member for Amgen, Astrazeneca, Janssen and Pfizer, and is a board member of 4 Therapeutics, Dynamic Cell Therapies, Next RNA, Starton Therapeutics and Window Therapeutics. N.L., H.L. and A.G. declare no competing interests.

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Neri, P., Leblay, N., Lee, H. et al. Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins. Nat Rev Clin Oncol (2024). https://doi.org/10.1038/s41571-024-00913-y

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