SOHO State of the Art Updates and Next Questions | Manuscript Title: Bispecific T-Cell Engagers: Sequencing, B-Cell Maturation Antigen, GPRC5D, and Resistance.

Bispecific antibodies (BsAbs) simultaneously engage endogenous T cells and malignant cells via binding to a T-cell epitope and an extracellular tumor antigen, leading to cytotoxic T-cell activity and tumor cell death. The incorporation of BsAbs into the treatment of multiple myeloma (MM) has improved options for patients with advanced relapsed MM. Three BsAbs have been approved by the Food and Drug Administration; 2 target BCMA on the surface of MM cells, while the other targets surface GPRC5D. Many other BsAbs are in development, including those that target antigens other than BCMA and GPRC5D, such as FcRH5, or that feature different binding constructs. As new BsAbs and new anti-MM agents in general become available, the question of sequencing these therapies becomes paramount. Moreover, resistance to therapy leading to disease relapse following initial response remains a major clinical obstacle, driving research into identifying mechanisms of resistance and developing approaches to overcome them. Understanding this topic will also guide how to best sequence therapies. Because BsAbs are dependent on T cell fitness, researchers are studying the concepts of employing combination therapies that improve T cell health, using a fixed duration of treatment to limit T cell exhaustion, and administering BsAbs earlier in the disease course.