Unlocking Drug Resistance in Multiple Myeloma: Adipocytes as Modulators of Treatment Response

SIMPLE SUMMARY: Worldwide obesity has nearly tripled in the last fifty years. Obesity is a risk factor for multiple myeloma, contributing to both an increased risk of multiple myeloma development and poor survival outcomes. Obesity is associated with the accumulation of fat cells (adipocytes) in bone marrow. These adipocytes can interact with, and modify the behavior of, nearby multiple myeloma cells. In this report, we found that adipocytes activate drug-resistance mechanisms in multiple myeloma cells, thus decreasing the effectiveness of anti-cancer drugs. The effects were more pronounced when adipocytes were derived from overweight or obese patients. Thus, we suggest a possible underlying mechanism by which obesity can allow for treatment failure and/or disease progression in multiple myeloma patients. ABSTRACT: Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of malignant plasma cells. Despite the development of a diverse array of targeted drug therapies over the last decade, patients often relapse and develop refractory disease due to multidrug resistance. Obesity is a growing public health threat and a risk factor for multiple myeloma, although the mechanisms by which obesity contributes to MM growth and progression have not been fully elucidated. In the present study, we evaluated whether crosstalk between adipocytes and MM cells promoted drug resistance and whether this was amplified by obesity. Human adipose-derived stem cells (ASCs) from nineteen normal (BMI = 20–25 kg/m(2)), overweight (25–30 kg/m(2)), or obese (30–35 kg/m(2)) patients undergoing elective liposuction were utilized. Cells were differentiated into adipocytes, co-cultured with RPMI 8226 or U266B1 multiple myeloma cell lines, and treated with standard MM therapies, including bortezomib or a triple combination of bortezomib, dexamethasone, and lenalidomide. We found that adipocytes from overweight and obese individuals increased cell adhesion-mediated drug resistance (CAM-DR) survival signals in MM cells, and P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) drug transporter expression. Further, co-culture enhanced in vitro angiogenesis, MMP-2 activity, and protected MM cells from drug-induced decreases in viability. In summary, we provide an underlying mechanism by which obesity can impair the drug response to MM and allow for recurrence and/or disease progression.