Emerging role of G protein-coupled receptor class C group 5 member D-directed immunotherapy in multiple myeloma: Advances, resistance and combination strategies.

Abstract

Multiple myeloma (MM) is a clonal malignancy of plasma cells characterized by frequent relapse and therapeutic resistance. G protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a promising immunotherapeutic target due to its high and selective expression in MM cells and minimal presence in normal tissues. This review outlines the structural features and expression profile of GPRC5D, emphasizing its relevance to disease biology and prognosis. We highlight recent advances in GPRC5D-targeted therapies, including antibody-drug conjugates (ADCs), bispecific and trispecific antibodies and chimeric antigen receptor T (CAR T)/natural killer (NK)-cell therapies, all demonstrating encouraging efficacy in relapsed/refractory MM. Key challenges, such as antigen escape and the need for optimized combination strategies, are also discussed. As GPRC5D-targeted agents advance through clinical development, large-scale prospective trials will be essential to define their therapeutic positioning and improve patient outcomes. GPRC5D is poised to become a leading next-generation target in MM immunotherapy following B-cell maturation antigen.