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