Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future

Abstract

Historically, the outcomes for individuals with triple-class refractory and penta-drug refractory multiple myeloma (MM) have been poor because of a dearth of effective treatment options. However, the advent of chimeric antigen receptor (CAR) T-cell and T-cell redirecting bispecific antibody (BsAb) therapies has led to unprecedented response rates and durations of response in heavily relapsed/refractory (R/R) populations. Currently, two B-cell maturation antigen (BCMA)-directed CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel) as well as one BCMA/CD3 BsAb (teclistamab) have been approved for late-line (greater than four previous lines) R/R MM in the United States. The purpose of this review is to analyze the recent data for these approved therapies as well as provide an overview of other related CAR T-cell and BsAb therapies under development, including non-BCMA-targeting agents. We review efficacy and safety considerations, with particular focus on cytokine release syndrome, neurotoxicity, and infection risk. The relative merits and limitations of each class of therapy are discussed, as well as the areas of unmet need with respect to optimal sequencing and supportive care measures. We examine the factors that challenge equitable access to these novel therapies across minoritized racial, ethnic, and socioeconomic populations. Although it is evident that CAR T-cell and BsAb therapies will transform treatment paradigms in MM for years to come, significant work remains to identify the optimal utilization of these novel therapies and ensure equitable access.

FIG 1.

Mechanism of action of CAR T-cell and BsAb therapies in MM. (A) The engineered CAR T cells recognize and engage with the target antigen (eg, BCMA) on the surface of the myeloma cell, leading to activation of the CAR T cell with subsequent release of perforin, granzymes, and cytokines, leading to cytolysis of the tumor cell. (B) A BsAb simultaneously engages the target antigen (eg, BCMA) on the myeloma cell as well as CD3 on the T cell, leading to an immunologic synapse and cytolysis of the tumor cell via release of perforin, granzymes, and cytokines. (C) Examples of the designs of several types of T-cell–redirecting agents developed as anti-BCMA therapies in MM. Currently only teclistamab, a BsAb, has achieved FDA approval for the treatment of relapsed/refractory myeloma. BCMA, B-cell maturation antigen; BiTE, bispecific T-cell engager; BsAb, bispecific antibody; CAR, chimeric antigen receptor; FDA, US Food and Drug Administration; MM, multiple myeloma; TCE, T-cell engager; TriTAC, trispecific T-cell–activating construct.