Bone-directed Therapeutic Targeting of Notch and Wnt Signaling Results in Profound Responses and Improved Bone Health in Multiple Myeloma 2

Multiple myeloma (MM) is a hematologic malignancy characterized by frequent relapses and debilitating bone disease, both of which pose significant therapeutic challenges. Here, we present a bimodal therapeutic strategy aimed at restoring aberrant Notch and Wnt signaling in the tumor microenvironment to stop disease progression and improve bone health in MM. Using clinically relevant mouse models and patient-derived samples, we demonstrate that co-treatment with a bone-targeted Notch inhibitor (BT-GSI) and romosozumab, a monoclonal antibody that neutralizes the Wnt antagonist sclerostin, effectively suppresses tumor growth, eliminates relapse-prone dormant residual cancer cells, and repairs bone. This strategy leads to long-term survival without significant toxicity. We also show the safety and bone repair efficacy of romosozumab in a cohort of MM patients in remission. Our findings highlight the anti-cancer, anti-resorptive, and bone anabolic effects of co-administration of BT-GSI and romosozumab, offering a promising approach to improve clinical outcomes in MM by simultaneously targeting multiple disease aspects.