Chronic intermittent hypoxia enhances disease progression in myeloma-resistant mice.

Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia (SH) or normoxia as a control in custom, gas permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10h/day of CIH (AHI=12/h), SH, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and SH slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67% versus 12%, p=0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival (p=0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared to the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.