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.

Natural killer cells affect the natural course, drug resistance, and prognosis of multiple myeloma

“…In March 2021, the FDA approved idecabtagene vicleucel (bb2121, targeting BCMA) for treating RRMM in adult patients after more than four treatment lines, including PIs, IMiDs, and anti-CD38 mAbs ( Sharma et al, 2022 ). The favorable response rate of CAR-T cells in RRMM has been summed up in several reviews ( Holstein et al, 2023 ; Parikh and Lonial, 2023 ; Zhang et al, 2023 ). However, the development of a sustained CAR-T cell response is still challenging, important potential processes include antigen loss, the generation of anti-CAR antibodies, and CAR-T cell exhaustion.…”

Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study

“…T-cell redirecting immunotherapies including bispecific antibodies (bsAbs) and chimeric antigen receptor T-cells (CAR T) therapy have transformed the treatment of relapsed/refractory multiple myeloma (MM) [1][2][3][4][5][6]. Notably, bsAb are off-the-shelf therapeutic options readily available to patients with aggressive disease relapse, with a lower incidence of severe acute toxicities such as cytokine release syndrome (CRS) or neurotoxicity, and potential ability to deliver treatment in the community, which can improve access to underserved populations [7]. Currently, two bsAbs targeting B-cell maturation antigen (BCMA) have received accelerated approval by the FDA-teclistamab and elranatamab [1,6].…”

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma

“…In recent years, autologous chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has risen as an important treatment option for relapsed/refractory (R/R) multiple myeloma (MM) [ 1 , 2 ]. Based on results from the phase 2 KarMMA trial, idecabtagene vicleucel (ide-cel) received US Food and Drug Administration approval for patients with at least four prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (mAb) [ 3 , 4 ]. Based on results from the phase 1b/2 CARTITUDE-1 trial, ciltacabtagene autoleucel (cilta-cel) was subsequently approved for the same indication [ 4 , 5 ].…”

“…Based on results from the phase 2 KarMMA trial, idecabtagene vicleucel (ide-cel) received US Food and Drug Administration approval for patients with at least four prior lines of therapy, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody (mAb) [ 3 , 4 ]. Based on results from the phase 1b/2 CARTITUDE-1 trial, ciltacabtagene autoleucel (cilta-cel) was subsequently approved for the same indication [ 4 , 5 ]. More recently, G protein-coupled receptor, class C, group 5, member D (GPRC5D) emerged as another actionable target in MM, with early-phase trials of GPRC5D-directed CAR T-cell products reporting promising outcomes [ 6 – 8 ].…”