The evolution of bispecific antibodies in multiple myeloma

The treatment of multiple myeloma (MM) has revolutionized over the last decade with the advent of CD38-targeting monoclonal antibodies such as daratumumab and isatuximab that were integrated into the therapeutic arsenal of patients with newly diagnosed or with relapsed and/or refractory (R/R) MM. Moreover, the advent of B-cell maturation antigen (BCMA)-targeting therapy continue to improve outcomes in patients with R/R disease. Multiple classes of these agents have been developed such as chimeric antigen receptor (CAR)-T cell therapy and antibody-drug conjugates. Another class of antigen-target therapy was the bispecific antibodies (BsAbs). The class, targeting CD20 and CD3, is now commonly used in patients with R/R B-cell lymphoma. It has also been developed for the treatment of patients with MM with other target antigens such BCMA, G protein-coupled receptor family C group 5 member D (GPRC5D), or Fc receptor-homolog 5 (FcRH5). Four BsAbs-teclistamab, elranatamab, linvoseltamab, and talquetamab-are currently approved by the Food and Drug Administration (FDA) for the management of patients with R/R MM. We review in this paper the most studied BiAbs, their mechanism of action, clinical activity, the mechanism of resistance. We discuss the place of BiAbs in the therapeutic arsenal of MM and the emergence of novel strategies such as combining two classes of BiAbs (for example teclistamab and talquetamab) or novel therapies such as trispecific antibodies to overcome resistance and increase the efficacy of BiAbs.