Bone marrow adipocytes (BMAd) have recently been implicated in accelerating bone metastatic cancers such as acute myelogenous leukemia and breast cancer. Importantly, bone marrow adipose tissue (BMAT) expands with aging and obesity - two key risk factors in multiple myeloma disease prevalence - suggesting that BMAd may influence and be influenced by myeloma cells in the marrow. Here we provide evidence that reciprocal interactions and cross-regulation of myeloma cells and BMAd play a role in multiple myeloma pathogenesis and treatment response. Bone marrow biopsies from MM patients revealed significant loss of BMAT with myeloma cell infiltration of the marrow, whereas BMAT was restored after treatment for multiple myeloma. Myeloma cells reduced BMAT in different pre-clinical murine models of multiple myeloma and in vitro using myeloma cell-adipocyte co-cultures. In addition, multiple myeloma cells altered adipocyte gene expression and cytokine secretory profiles, which were also associated with bioenergetic changes and induction of a senescent-like phenotype. In vivo, senescence markers were also increased in the bone marrow of tumor-burdened mice. BMAd, in turn, provided resistance to dexamethasone-induced cell cycle arrest and apoptosis, illuminating a new possible driver of myeloma cell evolution in a drug resistant clone. Our findings reveal that bi-directional interactions between BMAd and myeloma cells have significant implications for the pathogenesis and treatment of multiple myeloma. Targeting senescence in the bone marrow adipocyte or other bone marrow cells may represent a novel therapeutic approach for treatment of multiple myeloma.