Systems Modeling of Bortezomib and Dexamethasone Combinatorial Effects on Bone Homeostasis in Multiple Myeloma Patients

Osteolytic bone disease is one of the most debilitating manifestations of multiple myeloma (MM). Bortezomib is a proteasome inhibitor that shows both anticancer and bone anabolic properties and is being evaluated for its positive effects in MM patients with skeletal complications. Dexamethasone is a potent corticosteroid that is often given in combination with bortezomib for its antineoplastic effects; however, bone loss and osteoporosis are major adverse effects of long-term steroid-based therapies. In this study, a small systems pharmacological model was developed to integrate the bone anabolic effects of bortezomib with the osteolytic activity of dexamethasone in MM patients with bone disease. The final model parameters were all estimated with good precision. The interaction model is based on codifying multiple regulatory mechanisms of drug action and provides a platform for probing optimized bortezomib and dexamethasone combination dosing regimens to minimize skeletal side effects during myeloma therapy.