Acquired resistance to bispecific antibodies by genetic or epigenetic inactivation of the target in multiple myeloma

Abstract Bispecific antibodies targeting CD3 on T cells and GPRC5D on plasma cells (talquetamab) demonstrated promising efficacy in multiple myeloma, but acquired resistance usually occurs within a few months. Using a single-nucleus multi-omic strategy in 3 patients with acquired talquetamab resistance, we identified two mechanisms of GPRC5D inactivation, by bi-allelic genetic inactivation, or by long-range epigenetic silencing of its promoter and enhancer regions. Investigating the molecular profiles of target genes may help guiding the choice of immunotherapy and early detection of resistance in multiple myeloma.