Insights and Future Directions of GPRC5D Therapies in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by marked biologic and clinical heterogeneity. Despite major advances with proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, MM remains largely incurable, with most patients experiencing a disease course marked by sequential relapses eventually leading to patient death. This unmet need has accelerated development of T-cell–redirecting immunotherapies. G protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a promising therapeutic target because of its high expression on myeloma cells and limited expression in normal tissues. Unlike B-cell maturation antigen (BCMA), GPRC5D expression is often retained after BCMA-directed therapy, making it an attractive strategy for overcoming antigen escape and treatment resistance. Talquetamab, the first approved GPRC5D-targeting bispecific antibody, has demonstrated substantial efficacy in heavily pretreated relapsed/ refractory MM. Overall response rates in the pivotal MonumenTAL-1 trial reached 74% with weekly dosing and 69% with every-two-week dosing, with rapid onset of response and durable remissions and an overall manageable safety profile. Importantly, clinically meaningful activity was also observed in patients previously treated with BCMA-directed chimeric antigen receptor T-cell therapy or bispecific antibodies. Ongoing studies are evaluating GPRC5D-targeted bispecific antibodies, chimeric antigen receptor T-cell therapies, trispecific antibodies, and rational combination approaches. These strategies may expand therapeutic sequencing options and potentially move GPRC5D-directed therapies into earlier lines of MM treatment.