PROJECT SUMMARY The pillars of multiple myeloma (MM) therapy are DNA alkylators (cyclophosphamide, melphalan), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), glucocorticoids (dexamethasone, prednisone) and IMiDs (thalidomide, lenalidomide, pomalidomide). Despite achieving an initial response, patients inevitably relapse and MM remains incurable. More recently, remarkable responses have been obtained with immunotherapy: antibodies against CD38 (daratumumab), bi-specific antibodies or BiTEs to BCMA, CAR-T cells against BCMA. However, similarly to what observed with conventional therapy, none of these immune-oncology agents are curative. We believe that in order to improve patient outcome we need to better define the changes induced by the tumor on the surrounding immune cells and the effects that conventional and immunotherapy exert on the tumor and its microenvironment. Unfortunately, most preclinical studies are conducted on xenograft models lacking an immune system, or transiently reconstituted with human immune subsets and fail to capture the complex interaction between tumor and immune cells. Using the clinically predictive, fully immunocompetent Vk*MYChCRBN mouse model of MM we have generated, we discovered that sensitivity to anti-BCMA bispecific antibody is affected by high tumor burden, which drives excessive antigenic stimulation and T cell exhaustion. Combination therapies aimed to boost T cell function increase the short-term activity of the bispecific antibody, but mice eventually relapse with modest improve in overall survival. Surprisingly, the addition of cyclophosphamide proved very effective, by inducing a tempered but durative T cell activation which was curative in a fraction of mice. Based on our results in VkMYChCRBN MM we have designed a phase 1, randomized phase 2 clinical trial of a BCMA/CD3 bispecific antibody teclistamab with the addition either iberdomide or cyclophosphamide. In this proposal we aim to use the results of treating MM patients with either single agent teclistamab, or combinations with iberdomide or cyclophosphamide to credential the Vk*MYChCRBN MM model for T-cell directed immunotherapy. Finally, we will investigate factors that regulate the development of immunologic protection and cure after bispecific antibody therapy. Overall, these data will further credential the Vk*MYChCRBN mouse model of MM and inform the clinical development of bispecific antibodies in MM.

PROJECT NARRATIVE T-cell directed therapies are the most exciting recent advances in treatment of patients, but after the initial response patients inevitably relapse to this disease and myeloma remains incurable. We will credential a mouse model for developing novel combinations of drugs with T-cell directed treatments which will allow for their rapid clinical development. These studies will likely inform clinical practice on how combine standard of care agents with immunotherapy.