A structural framework for mutation-guided immunotherapy sequencing of GPRC5D-targeted T cell engagers in multiple myeloma

G-protein–coupled receptor family C group 5 member D (GPRC5D) is a leading immunotherapy target in multiple myeloma (MM), with diverse GPRC5D-targeting agents—including T-cell engagers (TCE), antibody–drug conjugates, and chimeric antigen receptor (CAR) T cells—being evaluated clinically for relapsed/refractory MM. In a recently published relapse cohort, 13 of 19 patients treated with anti-GPRC5D therapy had acquired GPRC5D alterations, with coding single-nucleotide variants or indels in 7 of these 13 patients [ 1 ]. Because GPRC5D-directed agents can bind distinct receptor regions, a single coding variant may have different implications for different drug formats, and the same relapse biopsy can encode either a target-class exit event or a mutation that disables only one antibody footprint. Current guidance supports BCMA- and GPRC5D-directed immunotherapy sequencing but remains largely target-based rather than mutation-based [ 2 , 3 ]. Clinically, relapse must be separated into surface loss, which argues against further GPRC5D targeting, and surface-expressed epitope escape, which may preserve alternate-epitope sensitivity. This raises a clinically urgent question: when a specific GPRC5D mutation is detected at relapse, which agent should the patient receive next?