PURPOSE: This study aimed to evaluate the influence of a supervised training program on the changes in serum monoclonal protein level (i.e., IgG), percentage of bone marrow plasma cells (BMPCs), fitness performance, and cardiac autonomic control (i.e., HR variability [HRV] and HR complexity [HRC]) in a female diagnosed with smoldering multiple myeloma (SMM). METHODS: A middle-age female patient with smoldering multiple myeloma and former elite athlete was monitored for 4 yr while participating in a supervised multimodal training regimen designed for the development of various physical capacities. The patient had the possibility of self-selection of daily training volume. Changes in fitness components, IgG levels, and BMPCs were evaluated throughout a 4-yr monitoring period (i.e., follow-up). HRV was examined via 24-h HR recordings during a 6-wk period at the second and the third year of the follow-up. RESULTS: Exercise performance in all fitness components was improved while IgG levels and BMPCs decreased (from 2.53 to 1.84 g . dL(-1) and from 20% to 10%, respectively). Time and frequency domain HRV parameters exhibited significant increases (18%-29%) with HRC remaining unchanged. CONCLUSIONS: The current case report results indicated that a multimodal training program designed for the development of various physical capacities improved exercise performance, hematological function, and cardiac autonomic control that may improve long-term prognosis for SMM. Examination of similar exercise training regimens for hematological and other cancer populations may assist in the development of simple nonpharmacological treatments for improved prognosis.