T-Cell Redirecting Antibodies for the Treatment of Multiple Myeloma: Off-the-Shelf T-Cell Immunity.

Abstract

Bispecific antibodies (BsAbs) bind simultaneously to an antigen on the surface of multiple myeloma (MM) cells and to CD3 on the surface of T cells. This engagement leads to T-cell activation and degranulation, releasing perforin and granzymes, followed by the killing of the MM cell. Off-the-shelf available BsAbs targeting BCMA, GPRC5D, and FcRH5 have pronounced antitumor activity in heavily pretreated MM with cytokine-release syndrome, neutropenia, and infections as the most common side effects. To further improve clinical outcomes, BsAb-based combinations are being evaluated in earlier treatment lines, including newly diagnosed MM. Notably, the MajesTEC-3 trial established the combination of teclistamab and daratumumab as a new standard-of-care for relapsed/refractory MM as early as first relapse. The most common mechanism underlying acquired resistance to BsAbs is loss of antigen expression; therefore, dual-targeting strategies (combination of BsAbs targeting different tumor antigens or trispecific antibodies) are being intensively investigated to enhance the depth and duration of response.