Early Intervention with Celmods, but Not Imids, Prevents Relapse to Forimtamig Driven By GPRC5D-Negative Myeloma Cells

Despite novel therapeutic options leading to a substantial increase in survival rates, multiple myeloma (MM) still represents an incurable disease. T cell bispecific antibodies (TCBs) have become a novel therapeutic option for relapsed refractory myeloma (RRMM) patients based on their promising objective response rates (ORR), favorable safety profile and off-the-shelf availability as compared to CAR-T cell therapies. Although BCMA- and GPRC5D-targeted TCBs have been reported to induce deep clinical responses, antigen drift represents a tumor intrinsic resistance mechanism limiting durability of responses 1. Here, we report that the combination of forimtamig, a 2:1 GPRC5D-targeted TCB, with CELMoDs, but not IMIDs, prevents tumor relapse driven by target-negative myeloma cells in a preclinical model of multiple myeloma. In order to mimic acquired TCB resistance in vivo, stem-cell humanized mice were engrafted with NCI-H929 tumors and treated once weekly (QW) with fixed duration forimtamig at 0.1 mg/kg for 6 cycles with a treatment-free follow up of more than 2 weeks. Single administration of forimtamig reduced tumor load by 80% at the end of cycle 1 (C1). At the end of cycle 4 (C4), all mice achieved a complete response (CR) with no detectable tumors. However, between C4 and cycle 6 (C6), tumor escape was observed in 47% of animals and progression free survival rate (PFS) at study termination was 53%. Relapsed tumors were subjected to quantitative immunohistochemistry and while prevalence for BCMA was comparable to baseline, GPRC5D expression was lost. To evaluate if cereblon modulation represents a strategy to improve PFS, we combined fixed-duration forimtamig with either pomalidomide (pom) or iberdomide (iber) at C1 day 1 (C1D1). Combination with pom and iber increased anti-tumor response compared to monotherapy during C1 deleting 88% and 92% of tumors, respectively. PFS for the combination with pom was not improved (~50%) as tumor escape was observed after treatment was stopped at C6. In contrast, no tumor relapse was observed for the combination with iber increasing PFS to 100%. Notably, as compared to forimtamig monotherapy, combination with pom and iber further increased serum levels of IFNg, IP-10, IL-2 and TNFa 48h after TCB dosing. We next explored if a sequential start of the combination would impact PFS and cytokine release and started co-administration at C3 instead of C1. Forimtamig induced strong tumor regressions in 90% of animals during C1-C4