Background: There is substantial evidence that the immune system is dysfunctional in multiple myeloma (MM). Adaptive immune cells, such as CD4⁺ and CD8⁺ T cells, are ineffective at controlling MM progression, suggesting immunosuppression. Therefore, efforts to overcome immunosuppression are likely key to more effective tumor control. Recent evidence from pre-clinical models suggests that exercise represents a non-pharmaceutical means to reduce immune exhaustion, but few studies have examined the relationship between an exercise intervention and biomarkers of immune exhaustion in cancer patients, especially in MM – the objective of this study. Methods: In this feasibility trial, 24 MM patients participated in a six-month physical activity intervention. The strength training arm (n=12) performed twice weekly supervised resistance trainings. The walking arm (n=12) engaged in an unsupervised, home-based wearable activity tracker intervention. Subjects provided peripheral blood samples before the start and at the conclusion of the intervention. Comprehensive flow cytometry was utilized to assess the frequency of mononuclear cells of interest, including CD4⁺ and CD8⁺ T cells and subpopulations expressing the markers of exhaustion PD-1 and/or TIGIT, which are the two exhaustion markers with the highest expression in this study sample. Ratios of exhausted cells (expressing any, one, or both of those markers) to non-exhausted cells (expressing no exhaustion markers) were calculated. Changes in the median values of these ratios were compared using Wilcoxon signed-rank tests. Results: Results from the immune panels are shown for the combined sample (n=24). All ratios of exhausted to non-exhausted cells were lower at the end of the six-month intervention, compared to baseline. The ratio of CD4⁺ TIGIT⁺ to non-exhausted CD4⁺ cells was significantly reduced, from 0.71 to 0.57 (p=0.04). The ratio of CD8⁺ PD-1⁺ to non-exhausted CD8⁺ cells was borderline significantly reduced, from 1.81 to 1.48 (p=0.06). Conclusions: This pilot study suggests that physical activity induces changes in MM patients’ immune systems, potentially rendering a less exhausted T cell state. Larger studies are warranted to examine how exercise alters activation vs exhaustion phenotypes within specific T cell subsets (naïve, central memory, effector memory, regulatory) and to elucidate the effects of strength-based vs aerobic exercise on T cell function.

¹Medians, interquartile ranges of ratios of exhausted CD4+ or CD8+ non-exhausted populations.