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survival (OS) and progression free survival (PFS) in MM patients. Furthermore, the preclinical activity of a new GPRC5DxCD3 bispecific antibody (JNJ-7564) in development for the treatment of MM was evaluated, as well as biomarkers for in vitro JNJ-7564 response. Methods: GPRC5D protein expression was assessed by flow cytometry on BM MNCs derived from healthy donors (HD) and MM patients. GPRC5D gene expression levels were analyzed in purified CD138 + MM cells derived from patients who participated in 5 large randomized clinical trials (HOVON65, MRC-IX, TT2, TT3 and APEX). MM cell lysis by JNJ-7564 (0.00064-4 µg/ml; 48 hour-incubation) was evaluated in MM cell lines and whole BM samples from newly diagnosed (ND) and relapsed/refractory (RR) MM patients. At baseline, the MNCs were characterized for the composition of T-cell subsets. T-cell activation and degranulation were measured by flow cytometry based on expression of CD25 and CD107a, respectively. Results: GPRC5D protein expression was significantly higher on MM cells compared to other BM cells, including HD plasma cells (fig 1A). GPRC5D protein expression was positively correlated with BCMA expression (r = 0.44; P = 0.02), but was independent of tumor load, and CD38 or PD-L1 expression on MM cells. Gene expression levels of GPRC5D were highly variable in MM, and independent of age and ISS stage, but were significantly higher in patients with t(4;14) or gain 1q. There was no association with OS or PFS in the 5 clinical trials (n = 1421). JNJ-7564 effectively killed GPRC5D + MM cell lines (MM1.S, UM9 (fig 1B) and RPMI8226) in a dose-dependent manner using HD peripheral blood MNCs as effector cells. Co-incubation with patient-derived BM stromal cells resulted in a modest impairment of killing capacity in MM1.S and RPMI8226 cells. In MM patient samples (n = 20), the mean lysis of MM cells with 4.0 µg/mL JNJ-7564 was 62% (range: −8-97%; fig 1C), while NK-cell and T-cell frequencies were not affected. JNJ-7564 was also effective in samples from extensively pretreated daratumumab (DARA)-refractory patients (DRMM; n = 6; median of 6 prior lines; mean lysis with 4.0 µg/mL: 70%; range: 44-97%). Maximal lysis of primary MM cells was not associated with the level of GPRC5D expression on MM cells, effector:target ratio, or frequency of regulatory T-cells. JNJ-7564-mediated MM cell lysis was associated with activation and degranulation of CD4+ and CD8+ T-cells (fig 1D).

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