An immunostimulatory CELMoD combination overcomes resistance to T-cell engagers caused by a high multiple myeloma burden Available to Purchase

• Hyper T cell activation driven by concurrent TCE+IMiD+anti-PD1 improves response rates in high tumor burden setting but drives lethal CRS

• Pretreatment with CELMoDs + DEX reshapes bone marrow T cell compartment and overcomes primary resistance to TCE.

Bispecific T cell engagers (TCE) targeting BCMA and CD3 induce deep hematologic responses in approximately 60% of heavily pre-treated multiple myeloma (MM) patients. We and others found that high tumor burden leads to resistance to TCE and novel strategies are urgently needed to improve responses in this setting. Ikaros-degraders, including IMiDs and CELMoDs, represent logical partners for TCE due to their direct anti-MM effects and additional immune stimulatory activity; however, it is unclear how to optimally combine them with TCE. Taking advantage of the immunocompetent IMiD-sensitive Vk*MYChCRBN murine model of MM, we optimized strategies to overcome primary resistance to BCMA-TCE and achieve sustained remission, while maintaining a manageable safety profile. The addition of anti-PD1 and pomalidomide reduced the T cell exhaustion that occurs in response to TCE in high tumor burden settings. This allowed for a higher degree of T cell activation and significant improvement in response rates but also increased risk of lethal cytokine release syndrome (CRS). To moderate the response and prevent CRS, we evaluated Ikaros-degraders and dexamethasone with step-up dosed TCE. Pre-treatment with iberdomide and dexamethasone reshaped the bone marrow T cell compartment, promoted infiltration of naïve T cells, and generated 100% response rates and the longest survival in subjects with high tumor burden. This was accompanied by more favorable T cell profiling, with limited expansion of regulatory T cells and exhaustion. In total, administering TCE following dexamethasone and iberdomide treatments provided deeper and more durable responses with reduced risk of CRS.