Acquired resistance to a GPCR5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation
Menée à partir d'échantillons sanguins et d'échantillons tumoraux prélevés sur trois patients atteints d'un myélome multiple et inclus dans un essai de phase I évaluant le talquétamab, cette étude met en évidence 2 mécanismes d'acquisition d'une résistance thérapeutique résultant de l'inactivation génétique ou épigénétique de la protéine transmembranaire GPRC5D
Bispecific antibodies targeting GPRC5D demonstrated promising efficacy in multiple myeloma, but acquired resistance usually occurs within a few months. Using a single-nucleus multi-omic strategy in three patients from the MYRACLE cohort (ClinicalTrials.gov registration: NCT03807128), we identified two resistance mechanisms, by bi-allelic genetic inactivation of GPRC5D or by long-range epigenetic silencing of its promoter and enhancer regions. Molecular profiling of target genes may help to guide the choice of immunotherapy and early detection of resistance in multiple myeloma.