S187: IMMUNOLOGICAL AGING HAS A NEGATIVE IMPACT ON CLINICAL OUTCOME IN ELDERLY MULTIPLE MYELOMA PATIENTS (2023)

Background: Multiple myeloma (MM) is a plasma cell malignancy which typically affects the elderly, with a median age of approximately 70 years. In healthy individuals, aging negatively affects the functional fitness of immune effector cells, such as T and NK cells. However, the impact of aging on the immune system in the context of MM and immunotherapy remains largely unclear. Aims: To better understand the impact of aging on the immune system in MM patients, we extensively 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: To assess differences between age groups, 261 newly diagnosed MM patients were included among which younger (range 34-65 years) and older (range 66-92 years) patients retrieved from the HOVON131 (EudraCT: 2014-004781-15) and HOVON143 (EudraCT: 2016-002600-90) trials, respectively. Within the older group, 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 UMAP and FlowSOM. Additionally, a lasso penalized logistic regression model was trained using cross validation to identify older patients with an immune profile more comparable to younger patients based on T cell metaclusters identified by FlowSOM. Survival differences were evaluated in the HOVON143 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 (Figure 1A). 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. In-depth analysis of T cell metaclusters identified by FlowSOM confirmed these findings and revealed two additional cell populations that differed between older and younger patients: one representing decreased naive γδ T cells and the other increased CD38+ Tregs in older patients (Figure 1B). When investigating intermediate fit and frail patients in more detail, we identified a higher PD1 expression on CD4+ T cells, particularly in the stem cell memory and central memory subsets, in frail compared with intermediate fit patients (Figure 1C), which was independent of age. Preliminary results of the penalized regression model identified 21% of older patients having a younger T cell profile. Notably, these patients had a superior overall survival (HR 3.2; 95% CI 1.26-7.98, p = 0.0098) and progression free survival (HR 1.8; 95% CI 1.07-2.97 p = 0.03) compared with their peers (Figure 1D), independent of age, ISS stage and high risk cytogenetics. Frail patients were underrepresented in the group with a younger T cell profile compared with intermediate fit patients (10% vs 33%, p =0.002). Summary/Conclusion: Older and frail MM patients displayed a distinct T cell profile compared with younger patients. Importantly, we identified a subgroup of older patients having a younger T cell profile, which was associated with superior survival. These new insights may further improve tailoring immunotherapies for older MM patients.Keywords: Aging, Multiple myeloma, Immunology