Loss of GPRC5D enhances the proliferative capacity and competitive fitness of myeloma upon anti-GPRC5D immunotherapy

Immunotherapies targeting surface antigens have transformed the treatment landscape of multiple myeloma (MM), with GPRC5D emerging as a promising therapeutic target. Monoallelic loss of GPRC5D is frequently observed in newly diagnosed MM patients, and the incidence of acquired GPRC5D alterations increases following exposure to GPRC5D-directed therapies. However, the functional consequences of both baseline monoallelic and therapy-induced biallelic GPRC5D alterations remain poorly understood. In this study, we modeled monoallelic versus biallelic loss of GPRC5D to investigate their impact on MM cell biology and responsiveness to GPRC5D-targeted immunotherapies. Our results demonstrate that monoallelic GPRC5D loss in OPM-2 cells reduces surface expression of the antigen and confers resistance to GPRC5D-directed therapies. Complete loss of GPRC5D alters the transcriptional state of MM cells and promotes reprogramming of the phosphoproteomic circuitry ultimately resulting in a pro-proliferative chemokine environment. As a result, GPRC5D deficiency increases the basal proliferation rate of MM cells thereby providing a competitive advantage which may further be amplified by selecting these aggressive phenotypes during ongoing treatment with anti-GPRC5D immunotherapies.