B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches

Abstract

Despite considerable advances in the treatment of multiple myeloma (MM) in the last decade, a substantial proportion of patients do not respond to current therapies or have a short duration of response. Furthermore, these treatments can have notable morbidity and are not uniformly tolerated in all patients. As there is no cure for MM, patients eventually become resistant to therapies, leading to development of relapsed/refractory MM. Therefore, an unmet need exists for MM treatments with novel mechanisms of action that can provide durable responses, evade resistance to prior therapies, and/or are better tolerated. B-cell maturation antigen (BCMA) is preferentially expressed by mature B lymphocytes, and its overexpression and activation are associated with MM in preclinical models and humans, supporting its potential utility as a therapeutic target for MM. Moreover, the use of BCMA as a biomarker for MM is supported by its prognostic value, correlation with clinical status, and its ability to be used in traditionally difficult-to-monitor patient populations. Here, we review three common treatment modalities used to target BCMA in the treatment of MM: bispecific antibody constructs, antibody-drug conjugates, and chimeric antigen receptor (CAR)-modified T-cell therapy. We provide an overview of preliminary clinical data from trials using these therapies, including the BiTE® (bispecific T-cell engager) immuno-oncology therapy AMG 420, the antibody-drug conjugate GSK2857916, and several CAR T-cell therapeutic agents including bb2121, NIH CAR-BCMA, and LCAR-B38M. Notable antimyeloma activity and high minimal residual disease negativity rates have been observed with several of these treatments. These clinical data outline the potential for BCMA-targeted therapies to improve the treatment landscape for MM. Importantly, clinical results to date suggest that these therapies may hold promise for deep and durable responses and support further investigation in earlier lines of treatment, including newly diagnosed MM.

Multiple myeloma with central nervous system relapse

“…These products, like CAR-T, have shown efficacy in RRMM. 78 However, unlike CAR-T, they have the advantage of not requiring ex vivo manipulation of patients' cells, therefore conferring a significantly faster time-to-treatment following diagnosis. Studies have suggested sBCMA is not just a suitable target for drug therapy but that it may also have an important role in MM as a biomarker at diagnosis for its prognostic value, in assessment of response to therapy, and in minimal residual disease monitoring.…”

Trends in the multiple myeloma treatment landscape and survival: a U.S. analysis using 2011–2019 oncology clinic electronic health record data

“…Despite all these agents leading to improved outcomes and patients living longer, patients eventually relapse, and multiple myeloma remains an incurable disease [9]. Multiple myeloma management is rapidly evolving as new therapies and modalities continue to be investigated and gain approval [10], with many investigational therapies using an immunotherapy approach, such as bispecific antibodies or chimeric antigen receptor T-cells, and with many potential therapies targeting B-cell maturation antigen (BCMA) [11][12][13].…”

Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?

“…The important roles of BAFF/APRIL and their receptors BCMA/TACI in MM make them potential therapeutic targets for the development of new treatment for relapsed/refractory MM. In recent years, a number of therapeutic modalities targeting BCMA, including antibody-drug conjugates (ADCs), T-cell redirecting bispecific molecules or antibodies and chimeric antigen receptor (CAR)-T cells have been developed and shown to demonstrate promising therapeutic effects preclinically and clinically [31][32][33]. However, some challenges, such as variable and often low level of BCMA expression on MM cells and antigen-negative tumor escape after initial BCMA-targeted immunotherapy, result in unsustained remission [31].…”

“…In recent years, a number of therapeutic modalities targeting BCMA, including antibody-drug conjugates (ADCs), T-cell redirecting bispecific molecules or antibodies and chimeric antigen receptor (CAR)-T cells have been developed and shown to demonstrate promising therapeutic effects preclinically and clinically [31][32][33]. However, some challenges, such as variable and often low level of BCMA expression on MM cells and antigen-negative tumor escape after initial BCMA-targeted immunotherapy, result in unsustained remission [31]. Thus, there is a need to explore other targets in this subgroup of ligands and receptors for the development of new modalities that can supplement or improve BCMA-targeted immunotherapy.…”