Immune Markers of Multiple Myeloma Patients Demonstrate Significant Change after Participation in Six-Month Physical Activity Intervention

Introduction

There is substantial evidence that the immune system is dysfunctional in multiple myeloma (MM), including immunoparesis and compromised, clonally related B-cells at various stages of differentiation. Effector cells, such as natural killer (NK) cells and cytotoxic CD8⁺ T cells, are present at expanded levels in MM but are seemingly ineffective at controlling disease progression, suggesting a state of immunosuppression. Recent evidence from pre-clinical models suggests pathways for exercise-induced immunomodulation. However, few studies have examined the link between exercise and immune biomarkers in patient populations. Herein, we examined the effect of an exercise intervention on markers of immune activation and exhaustion.

Methods

As part of this feasibility trial, 23 MM patients participated in a physical activity study and had immune markers measured before and after the intervention. The strength training arm (n=11) consisted of twice weekly individual, supervised resistance training targeting each of the major muscle groups, lasting for six months. The walking arm (n=12) was an unsupervised, home-based intervention. Participants in both arms were given a Fitbit with remotely programmed, progressive active minutes goals, with the overall goal of achieving 300 active minutes per week by the end of the six-month period. Subjects provided peripheral blood samples at multiple timepoints, including before the start of the intervention, at three months, and at the conclusion of the intervention, at six months. Comprehensive flow cytometry was utilized to assess the frequency of mononuclear cells of interest, including CD4⁺ and CD8⁺ T cells and their subsets, B cells and their subsets, NK and NK T cells, myeloid-derived suppressor cells (MDSCs), and monocytes. Appropriate ratios of the measures of interest were also calculated. Characteristics of the intervention arms were statistically compared using Student's t-test for differences in mean or chi-squared test of differences in proportion. Changes in immune markers of interest from baseline to end of intervention were compared using paired t-tests, with mean changes evaluated for the overall study and each of the two intervention arms.

Results

Results from the immune panels are shown in Table 1. The greatest immune profile changes from the start of the intervention to its conclusion were decreases in markers of exhausted CD8⁺ T cells, with 12 of 15 populations showing lower levels after the intervention, seven of which were reduced by >75%, and three of which showed a statistically significant decrease for the overall study group (CD8⁺TIM3⁺PD-1⁺, CD8⁺TIM3⁺LAG3⁺PD-1⁺, and CD8⁺TIM3⁺TIGIT⁺PD-1⁺). The overall group also showed significant decreases in the CD4⁺TIGIT⁺PD-1⁺ population and CD4⁺ central-memory T cells (TCM), and significant increases in CD4⁺ terminally differentiated effector-memory T cells (TEMRA) and monocytic MDSCs (M-MDSCs). The strength training vs. walking arms exhibited alterations in immune markers. More specifically, the strength training arm had a significant decrease in CD8⁺TIM3⁺PD-1⁺ cells and significant increases in CD4⁺ TEMRA cells and M-MDSCs. The walking arm had significant decreases in CD8⁺ T cells, CD4⁺ TCM, CD8⁺ TCM, CD4⁺TIGIT⁺PD-1⁺, and CD16/CD56^-CD57⁺ NKT cells, and significant increases in CD4⁺ T cells and the ratio of CD4⁺ to CD8⁺ T cells.

Conclusion

The current study presents evidence that physical activity might induce changes in the immune system of MM patients, causing a less exhausted T cell profile and other immune and myeloid changes. Larger studies are needed to determine if these results can be expanded and to elucidate the different effects of strength-based vs. aerobic exercise.

Hillengass:Sanofi: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: DSMB; GSK: Membership on an entity's Board of Directors or advisory committees; Curio Science: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Honoraria; Beijing Life Oasis Public Service Center: Honoraria; Beigene: Honoraria; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Adaptive: Honoraria; Skyline: Membership on an entity's Board of Directors or advisory committees.