PD-1 and LAG-3-positive T cells are associated with clinical outcomes of relapsed/refractory multiple myeloma patients

Objective: To investigate the frequency of PD-1 and LAG-3-positive T cells in relapsed/refractory multiple myeloma (RRMM) patients and its clinical significance. Methods: This prospective observational study enrolled a total of 71 RRMM patients, as well as 70 MM patients (non-refractory) and 70 healthy individuals during January 2018 to March 2021. The frequency of circulating CD4 and CD8 T cells expressing PD-1 and LAG-3 was analyzed using flow cytometry. Serum cytokines of IL-6, IL-17, CRP, TNF-α and TGF-β were evaluated by enzyme linked immunosorbent assay (ELISA). Results: Significant higher 1-year mortality rate was found in RRMM patients compared with the MM patients. In both CD4 and CD8 T cells, the frequencies of PD-1, LAG-3 and PD-1/LAG-3 T cells were markedly higher in the RRMM patients and the deceased patients, compared with the MM patients and the survival patients, respectively. All cytokines were remarkably higher in RRMM and MM patients than in the healthy control, while only serum levels of IL-6 and IL-17 were markedly higher in RRMM patients compared with the MM patients. Positive correlation was observed among the IL-6, IL-17 and the frequencies of circulating T cells in both CD4 and CD8 T cells in RRMM and MM patients. The frequency of CD8PD-1LAG-3 T cells showed the best sensitivity 82.61% and specificity 76.06% for diagnosis of RRMM using ROC curve. Meanwhile, the frequency of CD4PD-1 cells showed the best sensitivity 84.00% and specificity 97.35% for prediction of patients’ mortality by ROC curve. The frequencies of CD4PD-1, CD8PD-1/LAG-3, as well as IL-6, IL-17 and TNF-α were found as risk factors for incidence of RRMM in all MM patients. Conclusion: The frequency of PD-1 and LAG-3-positive T cells is associated with the clinical severity and inflammation in RRMM patients, which may also serve as potential biomarkers for its diagnosis.