Immunostimulatory CELMoD combination overcomes resistance to T cell engagers caused by high multiple myeloma burden

Bispecific T cell engagers (TCE) targeting BCMA and CD3 induce deep hematologic responses in approximately 60% of heavily pre-treated multiple myeloma (MM) patients. 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. Whole Bone Marrow single cell profiling of immune phenotype of untreated and treated de novo Vk murine model. Age matched de novo Vk*MYChCRBN mice with MM received vehicle, dexamethasone at 10 mg/kg, IBER at 10 mg/kg or combination. 23 hours later, mice were euthanized and BM cells collected. After ACK lysis, 8,000 mononuclear cells/sample were processed using the 10XGenomicsChromium single cell 3’V2 kit. For a subsequent repeat, we performed ACK lysis of samples from one mouse per treatment to obtain 5,000 mononuclear cells which were processed using the 10XGenomicsChromium automated single cell 5’v2 kit. Illumina libraries were sequenced on a partial Novaseq S4 lane to obtain 50,000 reads/cell. Gene counting was performed using Cell Ranger version 7.1.0 or higher.