Abstract A031: Dissecting the role of the bone ecosystem and intrinsic resistance in the evolution of refractory multiple myeloma
Authors: Miller Anna K. , Bishop Ryan T. , Li Tao , Lynch Conor C. , Basanta David 
Published: May 2022

Abstract
Multiple myeloma (MM) is a largely incurable cancer characterized by the expansion of plasma cells in the bone marrow. A key component of MM growth involves the establishment of a “vicious cycle” of enhanced bone resorption and tumor growth, resulting in extensive bone destruction and osteolytic lesions. Although there are many approved therapies that contribute to the long-term survival of patients, MM ultimately become refractory to treatment. The evolution of resistance is in part due to the bone ecosystem, which protects MM cells during treatment through interactions between the tumor cells and mesenchymal stem cells and cytokines secreted during bone resorption. The acquisition of refractory disease has also been attributed to intrinsic drug resistance, which allows for MM clones with inherent resistance to become the dominant population due to treatment-imposed selective pressures. While both the protective bone microenvironment and intrinsic drug resistance contribute to refractory disease, the role of the bone microenvironment in the development of cell intrinsic resistance has not been established and remains difficult to assess using current in vitro and in vivo methods alone. However, integration of cancer and evolutionary biology with computational modeling allows a unique insight into the spatiotemporal aspects of myeloma evolution and how treatment impacts the evolutionary dynamics of the disease. To explore these evolutionary dynamics, we developed a hybrid agent-based model that incorporates key cellular species that drive normal bone remodeling and, in the context of cancer, create an environment that provides protection. We use published data as well as our own to calibrate parameters such as the bone mineralization rate and to compare cell population dynamics to model outputs. Furthermore, we incorporate spatial data from immunofluorescence imaging of bone to motivate model assumptions on the localization of dividing and dying MM cells. We show that our model captures two key features: normal bone homeostasis, and the myeloma-bone vicious cycle. We then examine how the bone ecosystem impacts the growth dynamics of MM cells and the degradation of bone under standard of care treatments such as bortezomib, an anticancer therapy. Specifically, we test how the spatial distribution of the cells and factors that provide protection, as well as the timing and dose of treatment, impacts treatment response. Our data demonstrates that resistant disease cannot develop without myeloma intrinsic mechanisms, however, protection from the bone microenvironment dramatically increases the likelihood of intrinsic resistance developing. This model provides a foundation to explore how ecological and evolutionary dynamics in the bone ecosystem and MM contribute to drug resistance and tumor growth which ultimately has the potential to help improve treatment strategies.
Citation Format: Anna K. Miller, Ryan T. Bishop, Tao Li, Conor C. Lynch, David Basanta. Dissecting the role of the bone ecosystem and intrinsic resistance in the evolution of refractory multiple myeloma [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A031.