CD8⁺CD38⁺ T cells identify functional high-risk multiple myeloma after autologous transplant: BMT CTN 0702 correlates

Patients with multiple myeloma (MM) who experience early relapse (ER) within 24 months of autologous stem cell transplantation (ASCT) have inferior overall survival and represent a functionally high-risk (HR) subgroup. To investigate immune features of functionally HR MM, we performed immunohistochemistry (IHC) of the bone marrow and high-dimensional flow cytometry-based phenotyping of peripheral blood to evaluate the T-cell compartment of patients with MM at day 100 after ASCT. An initial IHC-based analysis of a cohort of patients with MM (n = 110) with long-term follow-up implicated CD3⁺PD-1⁺ T cells as a marker of functionally HR disease independent of maintenance therapy or cytogenetics, suggesting a role for activated T cells as a biomarker of disease biology. Next, to further refine the immunophenotype associated with ER, we conducted flow cytometry of peripheral blood samples from Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 trial participants with ER (n = 45) or long-term remission (LR; n = 51), defined as no relapse for >4 years of follow-up. Unsupervised clustering followed by multivariate logistic regression identified the differential expression of HLA-DR, granzyme B, CTLA4, CD27, TIGIT, and CD38 within discrete T-cell subsets, distinguishing ER from LR patients. After variable reduction and validation, CD38 expression by CD8⁺Eomes⁺ effector memory T cells emerged as the most predictive feature segregating ER from LR patients, with an area under the curve (AUC) of 86%. This immunophenotype was corroborated in a separate standard-of-care cohort (n = 18). Thus, flow cytometric analysis of peripheral blood at day 100 after ASCT identified a CD8⁺CD38⁺ T-cell subpopulation as a key feature of immunologically HR MM.