SEMINAR: Development of a Mathematical Modeling Platform to Explore Effects of Different Drug Treatments in Patients with Multiple Myeloma

Multiple Myeloma (MM) is an incurable blood cancer with 70% of patients exhibiting osteolytic bone lesions. Besides use of bisphosphonates such as Pamidronate, a couple of novel targeted agents such as Denosumab have shown great promise to improve MM-driven bone loss. Just recently, an integrated cellular bone homeostasis model for Denosumab pharmacodynamics in MM patients has been proposed. However, no comparison with different drugs and/or treatment regimes has been made. Hence, in this presentation we aim to develop a computational modeling platform to explore comprehensive effects of different drug treatments in MM patients. In order to do this we first build a “mechanistic” mathematical model to clearly identify „vicious cycles‟ between MM cells and the bone microenvironment. In the second step we couple this model with pharmacokinetic models in order to be able to see the effects of different drug treatments on changes in physiologically measurable quantities such as cell numbers, bone markers and bone volume.

In this study, we are focusing on three particular candidates for the formation of vicious cycles between MM cell and bone cells: (i) RANK/RANKL/OPG pathway; (ii) Wnt/Frz/LRP5 pathway; (ii) TGF-be; The first vicious cycle is driven via PTHrP and/or RANKL produced by MM cells directly or indirectly to stimulate NF-kappa-be signaling leading to increased osteoclast formation; The second cycle is related to the inhibitory action of Dkk1 produced MM cells which prevents differentiation/proliferation of osteoblast precursor cells and so leads to a decrease of active osteoblasts; The third vicious cycle is related to the stimulatory action of TGF-be on MM cell proliferation/differentiation.