Summary Multiple myeloma (MM) is characterized by the growth of malignant plasma cells in the bone marrow supported by increased angiogenesis. Despite significant advances in treatments, MM remains incurable due to frequent relapses originating from MM cells refractory to therapy. Further, MM induces a devastating bone disease, increasing fracture risk and decreasing quality of life. The long-term goal of this proposal is to improve clinical outcomes in MM by defining targetable mechanisms underlying MM growth, responses to therapy, and bone destruction. The rationale stems from work from the previous funding period demonstrating that osteocytes (Ots) are an abundant and long-lived source of signals in the MM tumor microenvironment (TME) that supports MM growth and promote bone destruction; and that targeting Ot-MM cell interactions decreases MM growth and improves bone health. In studies leading to this application, we found that MM cells upregulate the expression of Fibroblast growth factor (FGF) 23 in Ots and discovered that Ots support angiogenesis and promote resistance to Bortezomib-based therapies. The specific goal of this proposal is to evaluate the efficacy of targeting local FGF23 derived from Ots to decrease tumor growth, repair damaged bone, and improve responses to therapy in MM. The central hypothesis is that Ot-derived FGF23 promotes MM progression, bone destruction, and refractory disease via local TME autocrine and paracrine signals mediated by the FGF23 co-receptor α-Klotho (αKL). This hypothesis will be tested in three specific aims: (1) Determine the contribution of Ot-derived FGF23 to MM tumor growth and bone disease by interfering with paracrine and/or autocrine FGF23-αKL signaling; (2) Determine the impact of Ot-derived Vascular endothelial growth factor A (VEGFA), a downstream target of FGF23, and other osteocyte-derived pro-angeogenic factors on the pathological angiogenesis in the MM-TME; and (3) Determine the role of FGF23 and the FGF23 target gene Heparanase (HPSE) on TME-induced resistance to Bortezomib-based therapies in MM cells. These aims will be pursued using a combination of innovative in vitro, in vivo, and in silico approaches, including cell-specific genetic tools, pharmacological approaches, human MM xenograft and immunocompentent mouse models of MM, primary cells from MM patients, scRNAseq analysis, and mining of MM patient genetic/clinical databases.