Multiple myeloma (MM) is incurable, the 2nd most common blood cancer, and most common cancer that affects bone. It occurs preferentially in elderly, males, and African Americans. Agent Orange and toxic agents used in Vietnam and Gulf Wars increase MM risk. Thus, MM incidence is rapidly rising among veterans. MM cells interact with the bone niche to activate osteoclasts and inhibit osteoblasts, leading to skeletal destruction that seldom heals even in remission. The bone niche protects MM cells against treatment, leading to future relapses and incurability. Current treatments provide temporary disease control with inadequate new bone formation. Patients suffer from chronic bone pain and require long-term treatment with new choices needed at relapse. MM takes a major toll on the health of veterans and is a heavy financial burden on the VA system. Proteasome inhibitors (PIs) such as bortezomib (Btz) are the mainstay of MM therapy. They are the only drug class with bone anabolic effects, but their benefit is transient. We propose to increase PI efficacy by combining them with a sphingolipid-modulating drug, fingolimod, already FDA-approved for multiple sclerosis. Our data show that fingolimod dramatically increases efficacy of bortezomib both to inhibit tumors and stimulate bone formation in mouse xenograft models of human MM. The dual efficacy was seen with MM cells growing within bone marrow and as subcutaneous plasmacytoma. In both models, there was a significant new trabecular bone formation in the lumbar spine distant from tumor cells. The combination also inhibited the growth of MM cells isolated from Btz-refractory patients in ex vivo co-cultures. Repurposing the approved drug fingolimod and new analogs (Imods) is particularly attractive since they are safe for long-term use, conveniently available as pills, and can be rapidly and cheaply tested in clinical trials. Both Btz and fingolimod have FDA-approved analogs with higher specificity and better safety profiles. Our goal is a phase I/II clinical trial of PI + Imods in relapsed MM within 5 years. The present grant is designed to provide necessary preclinical data to support this trial. Aim 1 will test combinations of second-generation fingolimod analogs (siponimod, ozanimod, and ponesimod) and PI, carfilzomib, and compare to Btz + fingolimod. Three models will be used: subcutaneous and intravenous xenografts of human MM cell lines with different genetic risk factors, and a mouse model with an intact immune system. The models will be characterized in detail for a reduction in tumor burden and preservation/stimulation of bone formation. The most promising combination will be further tested in Aim 3 using primary MM samples. Aim 2 will investigate the mechanism of action of combination at concentrations achievable in patients. Fingolimod and other Imods may have indirect effects via the tumor niche or alter concentrations of systemic endocrine factors. We will test fingolimod effects on bone ...