Studies on multiple myeloma (MM), the second most common hematologic malignancy, have shown inconclusive results regarding the role of exercise in treatment. This study evaluated the relationship between physical exercise and MM treatment outcomes. In the 5T-MM mouse model, tumor-bearing mice underwent treatment that included bortezomib and dexamethasone alongside 6 weeks of low- or moderate-intensity treadmill aerobic training. Tumor burden and survival data were recorded. Additionally, a retrospective analysis was conducted on 65 MM patients undergoing maintenance therapy at West China Hospital from 2013 to 2024. Patients were categorized based on their adherence to the World Health Organization (WHO) physical activity guidelines, and progression-free survival and progression-free survival in maintenance therapy were analyzed. In the mouse model, the combination of dual-drug therapy and exercise improved outcomes, extending survival by more than 10 days. Aerobic exercises reduced regulatory T cells and increased NK cells in the peripheral blood of mice. In the exercise group of mice, myokines IL-15 and irisin were up-regulated, implying both myokines could contribute to the regulation of anti-MM immunity. In the patient study, patients who met the WHO physical activity recommendations demonstrated significantly better progression-free survival (PFS) and progression-free survival in maintenance treatment (PFSm). Overall, appropriate aerobic exercises may benefit some MM patients, suggesting a potential for exercise as an adjunct in MM treatment.© 2025 UICC.