Dr Rasche on BCMA and GPRC5D Loss After Bispecific Antibody Therapy in Multiple Myeloma

Leo Rasche, MD, attending physician on the myeloma service, University Hospital of Würzburg, Germany, discusses BCMA and GPRC5D loss after bispecific antibody therapy in multiple myeloma.

Genomics are known to play a role in resistance, but the exact mechanisms of resistance to bispecific antibodies and CAR T-cell therapy are not well defined, Rasche says. Biallelic alterations may present in the genes encoding for the antigens targeted by antimyeloma therapy. Investigators have previously shown that biallelic deletion of BCMA can result in antigen loss and resistance to CAR T-cell therapy, Rasche says. With the availability of BCMA- and GPRC5D-directed therapies like belantamab mafodotin-blmf (Blenrep) and talquetamab-tgvs (Talvey), investigators sought to evaluate the effects of sequential treatment with immunotherapy. 

At the 2023 International Myeloma Annual Meeting, Rasche presented a case study of a patient who received over 10 lines of treatment at the University Hospital Wurzburg in Germany, including BCMA- and GPRC5D-directed bispecific antibodies. The patient underwent whole-genome sequencing and was found to have biallelic deletion of BCMA and GPRC5D deletion, becoming double negative for both antigens, Rasche says.

This case study shows the potential for immunotherapy to become an evolutionary bottleneck, Rasche adds. These results suggest that investigators should consider a dual-targeted bispecific antibody to delay the likelihood of resistance rather than using these agents sequentially, Rasche concludes.