Unpacking Resistance to GPRC5D Therapy in Myeloma: What We've Learned

Rahul Banerjee, Assistant Professor at the Fred Hutchinson Cancer Center and at the University of Washington, shared a post by Nizar Jacques Bahlis, Associate Professor of Medicine at the University of Calgary, adding: “This entire Twitter thread is fascinating – everything we didn’t know about resistance to GPRC5D Tx (talq et al) in myeloma. Also this gem: as non-CLIA flow assays proliferate for BCMA and GPRC5D detection, worth noting that some flow-“neg” variants still tal-sensitive.” Quoting Nizar Jacques Bahlis‘s post: “Delighted to share a MonumenTal work led by Dr Holly Lee and many collaborations detailing the multimodal resistance mechanisms to anti-GPRC5D TCE in multiple myeloma out today in Nature Medicine. GPRC5D-targeted TCEs yield deep responses in RRMM, but most patients relapse. In this largest series to date, we show relapse arises through diverse genetic & epigenetic mechanisms converging on GPRC5D escape revealing strong evolutionary pressure from TCE therapy. We analyzed paired pre/post anti-GPRC5D TCE samples from 21 MM patients using WGS, scRNA/ATAC-seq, flow, imaging, and functional assays. This multi-omic approach captured both antigen-specific and antigen-agnostic escape, mapping how tumors adapt under TCE pressure. GPRC5D antigen escape was common: 13/21 relapses (61.9%) had GPRC5D alterations via SNVs/indels ± CN loss (n=7), focal/large CN loss (n=5), or epigenetic silencing (n=1). Different mechanisms converged on loss of surface antigen or altered the talquetamab binding epitope. Beside biallelic focal/ large deletions resulting in complete GPRC5D antigenic loss, remaining GPRC5D mutations fell into two functional classes, trafficking defects or binding epitope-altering variants. Mechanism #1: ER to membrane trafficking defects: SNVs/ indwells clustering in GPRC5D ER-trafficking motifs or frameshift/nonsense variants disrupting GPRC5D C-terminal ER export signal resulting in ER trapping and markedly reduced surface GPRC5D expression. Mechanism #2: anti-GPRC5D TCE-targeted epitope mutations: Other GPRC5D monoallelic mutations (p.Asp239Asn) preserve surface expression but alter Talq-binding, and when in-trans with truncating mutations of the remaining allele (p.Trp237Ter) result in complete resistance. Highlighting the relevance of adequate dosing & dose-dependent effect of certain mutants: higher concentrations of Talq partially restore its binding & cytotoxicity against GPRC5D p.Asp239Asn. This mutation does not impair the activity of dual-binding GPRC5D TCE Forimtamig. Limit of detection (LOD) and sensitivity to anti-GPRC5D TCEs: Some GPRC5D mutants (e.g., p.Tyr257Ser) result in low antigen surface expression below LOD of conventional flow cytometry however remain sensitive to GPRC5D dual-epitope targeting TCEs. Epigenetic GPRC5D silencing in B-cell like t(11;14): Coupled frameshift mutation with epigenetic PRC5D silencing mediated Talq resistance in t(11;14) MM. scATACseq profiling revealed reduced promoter & enhancer GPRC5D chromatin accessibly with lower mRNA in t(11;14) MM. Clinical implications i) resistance is multi-modal ii) Expression below flow LOD does not always equate to lack of TCE activity iii) adequate dosing or dual-epitope targeting TCEs overcome some resistant mutations iv) GPRC5D epigenetic silencing in B cell.”