Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma
Holly Lee, Sungwoo Ahn, Ranjan Maity, Noémie Leblay, Bachisio Ziccheddu, Marietta Truger, Monika Chojnacka, Anthony Cirrincione, Michael Durante, Rémi Tilmont, Elie Barakat, Mansour Poorebrahim, Sarthak Sinha, John A. McIntyre, Angela Chan, Holly Wilson, Shari Kyman, Amrita Krishnan, Ola Landgren, Wencke Walter, Manja Meggendorfer, Claudia Haferlach, Torsten Haferlach, Hermann Einsele, K. Martin Kortüm, Stefan Knop, Jean Baptiste Alberge, Andreas Rosenwald, Jonathan J. Keats, Leo Rasche, Francesco Maura, Paola Neri, Nizar J. Bahlis
Abstract
B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates multiple myeloma (MM) resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging data report that downregulation of G-protein-coupled receptor family C group 5 member D (GPRC5D) protein often occurs at relapse after anti-GPRC5D CAR T therapy. To examine the tumor-intrinsic factors that promote MM antigen escape, we performed combined bulk and single-cell whole-genome sequencing and copy number variation analysis of 30 patients treated with anti-BCMA and/or anti-GPRC5D CAR T/TCE therapy. In two cases, MM relapse post-TCE/CAR T therapy was driven by BCMA-negative clones harboring focal biallelic deletions at the TNFRSF17 locus at relapse or by selective expansion of pre-existing subclones with biallelic TNFRSF17 loss. In another five cases of relapse, newly detected, nontruncating, missense mutations or in-frame deletions in the extracellular domain of BCMA negated the efficacies of anti-BCMA TCE therapies, despite detectable surface BCMA protein expression. In the present study, we also report four cases of MM relapse with biallelic mutations of GPRC5D after anti-GPRC5D TCE therapy, including two cases with convergent evolution where multiple subclones lost GPRC5D through somatic events. Immunoselection of BCMA- or GPRC5D-negative or mutant clones is an important tumor-intrinsic driver of relapse post-targeted therapies. Mutational events on BCMA confer distinct sensitivities toward different anti-BCMA therapies, underscoring the importance of considering the tumor antigen landscape for optimal design and selection of targeted immunotherapies in MM.