Whole genome, RNA-seq and single-cell Multiome profile of multiple myeloma

Bispecific antibodies targeting CD3 on T cells and GPRC5D on plasma cells (talquetamab) demonstrate promising efficacy in multiple myeloma. However, disease progression frequently occurs within a year, and the mechanisms of acquired resistance are unknown. Here, we use a single-cell multi-omic strategy to explore the mechanisms of talquetamab resistance in two patients. In the first patient, a pre-existing 12p deletion encompassing GPRC5D locus allowed the emergence of seven resistant subclones at relapse, each harboring a distinct second hit leading to the bi-allelic inactivation of the target. In the second patient, resistant cells displayed a complete loss of GPRC5D expression due to the long-range epigenetic silencing of its promoter and enhancer regions. Thus, acquired talquetamab resistance can result from the genetic or epigenetic inactivation of GPRC5D. Investigating the molecular profiles of target genes may help guiding the choice of immunotherapy and early detection of resistance in multiple myeloma.EGA study EGAS00001007014