Immunotherapy has transformed the treatment landscape of multiple myeloma (MM), harnessing T-cell–mediated cytotoxicity with the promise of deep remissions and immune memory. Yet, immune escape remains a defining hallmark of cancer, and its effects are particularly relevant in MM, where prolonged sustained responses to cellular therapies occurs only in small fraction of patients. One underrecognized contributor to this limitation is immune senescence.

Aging of the adaptive immune system, characterized by the loss of naïve T and B cells and the accumulation of memory and senescent subsets, reduces vaccine immunogenicity, impairs immune reconstitution, and limits the expansion of CAR T-cells. While these effects are often attributed to chronological aging, emerging evidence suggests that malignancy itself and its treatments may independently accelerate immune senescence. MM patients often present with qualitative and quantitative T cell abnormalities, even at diagnosis, and are exposed to lymphotoxic agents during induction therapy. Whether immune aging is already measurably accelerated after frontline therapy but prior to hematopoietic cell transplantation (HCT) remains unclear. We sought to quantify immune aging in MM patients using donor-referenced models of naïve lymphocyte compartments, focusing on whether standard induction leads to an early and measurable immune-age gap.

Methods

We analyzed prospectively collected peripheral blood flow cytometry data from two cohorts: 219 MM patients who had completed a median of four cycles of PI/IMiD-based induction therapy (pre-HCT) and 150 healthy, related donors (pre-apheresis), enrolled between 2020 and 2024 in a single institute setting. Immunophenotyping was performed utilizing a 10-color panel (CD3/CD4/CD8/CD19/CD45RA/CCR7/CD56/CD16/HLA-DR/CD14) on a FACSCanto II. Naïve T cells (CD4⁺ or CD8⁺, CD45RA⁺, CCR7⁺) and CD19⁺ naïve B cells were identified, and their absolute counts log₂(x+1) transformed. Generalized additive models (GAMs) were fitted to donor data to model the nonlinear relationship between age and biomarker expression. These donor-derived splines were then inverted to estimate an “immune age” for each MM patient. Immune-age gaps were calculated as the difference between estimated immune age and actual age. Age × Cohort interaction terms were tested to determine whether the rate of decline with age differed between MM patients and donors. Immune age estimates were constrained within the donor age range (19–76 years) to avoid extrapolation bias.

Results

The MM cohort had a median age of 62 years (interquartile range [IQR] 55–68), while the donors had a median age of 46 years (IQR 32–57). CD4⁺ naïve T cells demonstrated a statistically significant Age × Cohort interaction (p value = 0.0064), indicating that MM patients exhibited a steeper age-related decline in this compartment than healthy donors. Although CD8⁺ naïve T cells and CD19⁺ naïve B cells showed apparent downward shifts in MM patients, their age × Cohort interactions did not reach statistical significance, potentially due to the limited overlap between cohort age distributions and model constraints at older ages. Immune-age gaps estimated via spline inversion revealed median age penalties of approximately +15 to +18 years across markers. Notably, MM patients under the age of 45 frequently displayed immune phenotypes resembling those of healthy donors aged ≥ 65 years. Some immune-age estimates for older patients clustered at the upper bound of 76 years, reflecting limitations in extrapolation due to the non-overlapping nature of the data. These results suggest that immune compromise in MM is not only present at diagnosis but amplified by induction therapy, particularly in the CD4-naïve T cell pool.

Conclusions

Following standard induction therapy, MM patients exhibit features of accelerated immune aging,most notably in the CD4⁺ naïve T-cell compartment corresponding to a one- to two-decade increase in immune age compared to the healthy donors. These immune-age gaps may impact vaccine responses and cellular therapy outcomes, warranting further study into rejuvenative or naïve-preserving strategies such as IL-7 agonism or earlier leukapheresis collection. Future clinical trials may benefit from incorporating immune age as a stratification or eligibility biomarker.

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2025
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