Exercise-mobilized lymphocytes enhance antibody-based immunotherapy in multiple myeloma through CD16+ NK cell–mediated cytotoxicity

Immunotherapies have significantly improved treatment outcomes in multiple myeloma (MM); however, challenges remain due to variable efficacy, toxicities, and off-target effects. Exercise-induced lymphocyte mobilization presents a novel adjunctive strategy to enhance immune-based cancer therapies. This study aimed to determine if lymphocytes mobilized by acute exercise could synergize with established MM therapeutic regimens to improve anti-myeloma cytotoxicity. We used an ex vivo model to assess the cytotoxicity of resting and exercise-mobilized lymphocytes against drug-sensitive (MM1.S) and resistant (MM1.R) MM cell lines in combination with established MM therapeutic regimens—lenalidomide and dexamethasone combined with either daratumumab (DRd) or magrolimab (MRd). Blood lymphocytes were collected from twenty-two healthy participants at rest and during 20-minutes of graded cycling exercise. An ex vivo approach was used to model two clinically relevant scenarios: (1) a pre-treatment approach prior to exercise-mobilized donor lymphocyte infusion (DLI-X) and (2) a co-treatment approach mimicking exercise during ongoing therapy. Exercise-mobilized lymphocytes demonstrated enhanced cytotoxicity against both drug-sensitive (MM1.S: ≤ 2.3-fold) and resistant (MM1.R: ≤ 2.4-fold) cell lines, which was further augmented by DRd or MRd (≤ 2.4-fold for MM1.S and ≤ 1.9-fold for MM1.R). In the co-treatment setting, NK-cells purified during exercise were more effective than resting NK-cells at mediating antibody-dependent cellular cytotoxicity (ADCC) with daratumumab (≤ 1.6-fold increase) and magrolimab (≤ 1.2-fold increase). This effect reflected the preferential mobilization of CD16+ NK-cells (≤ 6.83-fold from rest), as CD16 blockade substantially diminished the exercise-induced ADCC enhancement (≤ 6.3-fold reduction). Cytotoxicity was greater in MRd versus DRd, likely reflecting daratumumab-induced fratricide of CD38+ NK-cells (≤ 1.4-fold decrease), which was particularly evident among exercise-mobilized NK-cells. These findings demonstrate that acute exercise mobilizes a potent NK cell subset that enhances monoclonal antibody efficacy against myeloma cells. These findings also highlight the potential for carefully timed and context-specific integration of exercise to optimize monoclonal antibody efficacy in MM. This study was conducted as part of the ‘Exercise as an Immune Adjuvant for Allogeneic Cell Therapies (Allo-X)’ trial, registered on 2024-10-16 at ClinicalTrials.gov, NCT06643221.