Trial-level association between age-enriched populations and treatment effect in frontline randomized multiple myeloma studies.

Abstract

e19555 Background: Age at diagnosis has traditionally been considered a host-related factor in MM, influencing treatment tolerability and competing mortality. However, emerging biologic and clinical observations raise the possibility that age-enriched trial populations may differ in disease behavior and treatment responsiveness. We performed a trial-level comparative analysis to evaluate whether median age of enrolled populations is associated with treatment effects across contemporary frontline randomized MM trials. Methods: We systematically assembled a dataset of 18 randomized frontline multiple myeloma clinical trials reporting treatment outcomes and baseline demographic characteristics. Trial-level median age was extracted for each study. The primary analysis used inverse-variance weighted meta-regression to evaluate the association between median age and log(HR) for PFS. A prespecified sensitivity analysis additionally adjusted for baseline control-arm risk using PFS-12 as a proxy. Exploratory analyses evaluated the robustness of findings across selected trial characteristics. Results: Among the 18 identified frontline trials, 14 trials reported sufficient data for inclusion in the primary inverse-variance meta-regression, and 13 trials were included in the sensitivity analysis adjusting for baseline risk. Median age across included trials ranged from approximately 57 to 73 years, reflecting systematic age enrichment across trial populations. In inverse-variance weighted meta-regression, median age demonstrated a modest positive association with log(HR) for PFS, indicating that trials enrolling younger populations tended to show greater relative PFS benefit from experimental therapies compared with trials enrolling older populations. The age association remained directionally consistent after adjustment for baseline risk and in exploratory analyses accounting for trial characteristics, suggesting that differences in control-arm efficacy or selected trial features alone do not fully explain the observed pattern. However, the magnitude of the association was small and substantial heterogeneity was observed across trials. Conclusions: In this trial-level analysis of frontline randomized multiple myeloma studies, age-enriched trial populations demonstrated a modest association with observed PFS treatment effects, with younger-enriched trials tending to show greater benefit from treatment intensification. While exploratory, the consistency of the association across sensitivity analyses suggests that age-related differences in treatment responsiveness may contribute to variability in outcomes across trials. These findings remain hypothesis-generating and do not establish age as an independent prognostic or biologic determinant at the patient level.