Obesity Accelerates Multiple Myeloma Progression in Certain Mouse Models and in Humans.

Severe obesity is positively associated with the risk of multiple myeloma (MM) and mortality; thus, obesity has emerged as a target for MM prevention. Established dietary-based mouse models have proven useful in recapitulating obesity-related diseases in humans, but the multifaceted nature of obesity, cancer, and mouse models has led to a knowledge gap regarding which myeloma models can capture obesity-accelerated cancer. Thus, we tested the effect of obesity on MM in three high-fat diet (HFD) murine MM models: a SCID-beige MM.1SGFP+/Luc+ xenograft, a C57BL/6J Vk*MYC syngeneic, and a C57BL/6J 5TGM1-TKGFP+/Luc+ semi-syngeneic. Only the third model recapitulated obesity-accelerated MM, where incidence rates, serum IgG levels, and bioluminescent tumor signal in HFD-fed mice were significantly higher than controls. This HFD-C57BL/6J 5TGM1-TKGFP+/Luc+ model is the first bioluminescent assessment of myeloma engraftment in obese mice and allows for non-invasive spatiotemporal tumor tracking of features such as tumor growth and clearance. It can now be used to test the role of the immune system, or other factors, in obesity-accelerated myeloma. Finally, our analyses of Multiple Myeloma Research Foundation (MMRF) CoMMpass clinical data showed associations of moderate and severe obesity at diagnosis with increased patient mortality and revealed novel gene expression and pathway signatures that differed between MM cells from obese and normal patients. Overall, our work supports the hypothesis that obesity contributes to myeloma disease progression in humans and provides a novel mouse model with which to study this.