Mechanisms of acquired GPRC5D resistance following talquetamab in RRMM

Results from a multi-institutional translational analysis, published in Nature Medicine by Lee et al., evaluated mechanisms of resistance to talquetamab, a G-protein-coupled receptor family C group 5 member D (GPRC5D)-directed T-cell engager (TCE), in patients with relapsed/refractory multiple myeloma (RRMM). The study evaluated patients who progressed following talquetamab therapy (N = 21). The primary objective was to define tumor-intrinsic mechanisms of GPRC5D antigen escape at relapse using integrated multi-omic profiling.

Key data: The median progression-free survival (PFS) in the overall cohort was 12.1 months (95% confidence interval [CI], 8–18.1 months). Genomic analyses identified GPRC5D alterations in 61.9% of patients; excluding primary refractory cases, the antigen escape rate was 68.4%. Three resistance patterns were observed: GPRC5D single-nucleotide variants (SNV)/insertion/deletions (indel) with or without copy number changes (n = 7), focal-to-large biallelic deletions spanning GPRC5D (n = 5), and epigenetic silencing coupled with a truncating mutation (n = 1). A subset of patients experienced relapse without detectable GPRC5D alterations (n = 6), suggesting non-antigen-mediated mechanisms may also occur.

Key learning: Acquired GPRC5D antigenic drift appears to be a common mechanism of resistance following treatment with talquetamab. These findings have potential implications for sequencing immunotherapies, and support ongoing evaluation of multi-epitope and multi-antigen targeting strategies in RRMM.