Chimeric Antigen Receptor Therapy in Multiple Myeloma

Although there have been significant improvements in the treatment of myeloma over the past decade that have translated to increased overall survival, most patients inevitably experience relapse of their disease. For patients with triple-class refractory multiple myeloma, or myeloma that is refractory to immunomodulatory imide drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies, there have been limited efficacious treatment options and a generally poor prognosis. Recent investigations of chimeric antigen receptor (CAR) T-cell therapies, primarily targeting the B-cell maturation antigen (BCMA), have demonstrated impressive overall response rates and durability of response in patients with heavily pretreated multiple myeloma compared to other currently U.S. Food and Drug Administration (FDA)–approved therapies for such patients with triple-class refractory multiple myeloma. This chapter reviews CAR construct characteristics, dosing strategies, and outcomes of safety and efficacy for several of the promising autologous anti-BCMA CAR T-cell therapies currently being investigated for the treatment of multiple myeloma. Included is a detailed review of the development and clinical studies involving idecabtagene vicleucel, the first FDA-approved CAR T-cell therapy for myeloma as of March 2021. This chapter also summarizes ongoing investigations of autologous anti-BCMA CAR T-cells in various lines of therapy, examines mechanisms of resistance to such therapies and strategies being explored to overcome resistance such as multiple/alternative antigen targeting and combination therapies, highlights unique toxicities associated with anti-BCMA CAR T-cell therapy, and reviews ongoing investigations of allogeneic CAR T-cell therapies for the treatment of multiple myeloma.