Computational modeling of interactions between multiple myeloma and the bone microenvironment.

Multiple Myeloma (MM) is a B-cell malignancy that is characterized by osteolytic bone lesions. It has been postulated that positive feedback loops in the interactions between MM cells and the bone microenvironment form reinforcing 'vicious cycles', resulting in more bone resorption and MM cell population growth in the bone microenvironment. Despite many identified MM-bone interactions, the combined effect of these interactions and their relative importance are unknown. In this paper, we develop a computational model of MM-bone interactions and clarify whether the intercellular signaling mechanisms implemented in this model appropriately drive MM disease progression. This new computational model is based on the previous bone remodeling model of Pivonka et al., and explicitly considers IL-6 and MM-BMSC (bone marrow stromal cell) adhesion related pathways, leading to formation of two positive feedback cycles in this model. The progression of MM disease is simulated numerically, from normal bone physiology to a well established MM disease state. Our simulations are consistent with known behaviors and data reported for both normal bone physiology and for MM disease. The model results suggest that the two positive feedback cycles identified for this model are sufficient to jointly drive the MM disease progression. Furthermore, quantitative analysis performed on the two positive feedback cycles clarifies the relative importance of the two positive feedback cycles, and identifies the dominant processes that govern the behavior of the two positive feedback cycles. Using our proposed quantitative criteria, we identify which of the positive feedback cycles in this model may be considered to be 'vicious cycles'. Finally, key points at which to block the positive feedback cycles in MM-bone interactions are identified, suggesting potential drug targets.