PhD-Candidate Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands, United States
Introduction: Multiple myeloma (MM) typically affects the elderly, with a median age at diagnosis of 69 years. In healthy individuals, aging negatively affects the functional fitness of immune effector cells. However, the impact of aging on the immune system in MM patients remains largely unclear. We therefore profiled the phenotype of T and NK cells related to age and frailty status. Within the older patients, we then sought for the existence of patients with a younger immune profile, and evaluated whether this impacted survival.
Methods: 261 newly diagnosed MM patients were included among which younger (range 34-65 years) and older (range 66-92 years) patients retrieved from the HO131 (EudraCT: 2014-004781-15) and HO143 (EudraCT: 2016-002600-90) trials, respectively. Older patients were further classified as intermediate fit or frail according to the IMWG frailty score. Comprehensive immune-profiling of T and NK cells was performed by flow cytometry on study-entry peripheral blood (PB) and bone marrow (BM) samples (n=462). Data were analyzed using FlowSOM. Additionally, a lasso penalized logistic regression model was trained using cross validation to identify older patients with younger versus older immune profiles based on T cell populations identified by FlowSOM. Survival differences of these profiles were evaluated in the HO143 trial using Kaplan Meier and cox regression analysis.
Results: In both BM and PB, older patients displayed a distinct T cell profile compared with younger patients, while NK cell profiles were similar. Older patients showed increased frequencies of activated HLA-DR+CD4+ , CD38+ CD8+ and CD25+ CD8+ T cells, regulatory CD4+ T cells (Tregs) and senescent (CD28-CD57+KLRG1+) CD8+ T cells. Additionally, we observed a higher proportion of effector memory CD8+ T cells and a lower proportion of naive and central memory CD8+ T cells in older patients. Explorative analysis of T cell populations identified by FlowSOM confirmed these findings and additionally revealed decreased naive γδ T cells and increased CD38+ Tregs in older patients. Subgroup analysis of intermediate fit and frail patients revealed higher PD1 expression on CD4+ T cells in frail than in intermediate fit patients, independent of age. Preliminary results of the logistic regression model identified 13.3% of older patients having a younger T cell profile. Notably, these patients had superior overall survival (HR 3.7; 95% CI 1.16-11.85, p = 0.027) and progression free survival (HR 2.0; 95% CI 1.09-3.84 p = 0.026) in the HO143 trial compared with their peers, which was independent of age, ISS stage and cytogenetic profile.
Conclusions: Older MM patients had more differentiated, senescent, and activated T cells than younger patients. Importantly, we identified a subgroup of older patients having a younger T cell profile, which was associated with superior survival in the HO143 trial. These new insights may improve tailoring immunotherapies and risk stratification in older MM patients.
