Abstract B019: The bone microenvironment's impact on the heterogeneity of resistance to proteasome inhibitors in multiple myeloma

Abstract

Abstract Multiple myeloma (MM) is an osteolytic plasma cell malignancy that, despite being responsive to therapies such as proteasome inhibitors, frequently relapses. Understanding the mechanism and the niches where resistant disease evolves remains of major clinical importance. Cancer cell intrinsic mechanisms and bone ecosystem factors are known contributors to the evolution of resistant MM but the exact contribution of each is difficult to define with current in vitro and in vivo models. Using a novel bmathematical model that incorporates key cellular species of the bone ecosystem that control normal bone remodeling and, in MM, yields a protective environment we studied how, under therapy, the bone ecosystem contributes to the evolutionary dynamics of resistant MM under control and proteasome inhibitor treatment. Our results show that Environmentally-Mediated Drug Resistance (EMDR) might not be sufficient to explain resistant disease. But our results highlight the importance of EMDR in facilitating the emergence of resistance, and more importantly facilitating the survival of tolerant cells, allowing the tumor multiple routes for resistant disease. Our results also provide evidence that intervention with therapies targetting the bone ecosystem would significantly improve the ability of treatment to increase the time to progression for patients with multiple myeloma and, potentially, other diseases where EMDR plays a role. Citation Format: David Basanta, Ryan Bishop, Anna Miller, Conor C. Lynch, Matthew Froid, Ariosto S. Silva, Kenneth H. Shain. The bone microenvironment's impact on the heterogeneity of resistance to proteasome inhibitors in multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B019.