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

Severe obesity is positively associated with the risk of multiple myeloma and mortality; thus, obesity has emerged as a target for multiple myeloma 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 about which myeloma models can capture obesity-accelerated cancer. Thus, we tested the effect of obesity on multiple myeloma in three high-fat diet (HFD) murine multiple myeloma models: a SCID-beige MM.1SGFP+/Luc+ xenograft, a C57BL/6J Vk*MYC syngeneic model, and a C57BL/6J 5TGM1-TKGFP+/Luc+ semisyngeneic model. Only the third model recapitulated obesity-accelerated multiple myeloma, in which incidence rates, serum IgG levels, and bioluminescent tumor signals in HFD-fed mice were significantly higher than in controls. This HFD-C57BL/6J 5TGM1-TKGFP+/Luc+ model is the first bioluminescent assessment of myeloma engraftment in obese mice and allows for noninvasive 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 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 multiple myeloma 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. PREVENTION RELEVANCE: Obesity is associated with an increased risk of developing multiple myeloma; however, the underlying mechanisms are unknown. We demonstrated that obesity-accelerated multiple myeloma is coupled with immune disruptions in mice and that gene expression is altered in myeloma cells from patients with obesity, further implicating obesity as a critical modifier for prevention.