Summary Proteasome inhibitor (PI) therapy has been crucial to the improved survival of patients with multiple myeloma (MM). Unfortunately, primary and acquired resistance to PIs contributes to disease progression and death. Obesity and/or insulin resistance are risk factors for MM mortality. Dysregulated inflammatory and metabolic factors in the metabolic syndrome or its associated components (obesity/insulin resistance/dyslipidemia) decrease the efficacy of chemotherapeutics for various tumor types, and likely contribute to chemoresistance and disease progression in MM patients. Our preliminary studies suggest that oxidized low-density lipoprotein (OxLDL), an oxidatively modified lipoprotein that is elevated in the metabolic syndrome, may be a potent contributor to MM resistance to PIs. Since the MM microenvironment contains numerous granulocytic cells and monocytes that express myeloperoxidase (MPO), a potent mediator of LDL oxidation, MM cells are likely exposed to high levels of OxLDL in disorders associated with hypercholesterolemia/dyslipidemia. This notion is supported by our detection of OxLDL in close proximity to MM cells and MPO-expressing cells in bone marrow samples from newly diagnosed MM patients. We have observed in cell culture experiments that OxLDL potently suppresses MM cell killing by bortezomib (VELCADE), a frontline chemotherapeutic used to treat MM. We have preliminary evidence that OxLDL, protects MM cells from PI-induced cytotoxicity by restoring proteasome activity. The proposed project aims to reveal key pathways involved in mediating the protective effect of OxLDL against PI-induced MM cell killing, and evaluate the potential of suppressing elevated OxLDL levels associated with hypercholesterolemia/dyslipidemia to enhance MM responsiveness to therapeutic PIs.