Bridging the evidence gap in trial inclusion with real world safety profile assessment in relapsed/refractory multiple myeloma patients.

backgroundThe underrepresentation of key populations in clinical trials can create critical gaps in our understanding of treatment efficacy and the generalizability of safety outcomes across broader patient populations. Ensuring that therapies are rigorously tested in diverse cohorts, while maintaining patient safety within trials, is essential for achieving optimal outcomes for all patients, regardless of medical history or comorbidities. Advancing inclusivity in clinical trials therefore requires a critical reassessment of eligibility criteria. In this context, real-world evidence provides a valuable opportunity to inform clinical trial design by assessing the safety implications of including patients that are typically excluded.

methodsWe proposed a quantitative framework leveraging real-world data and adopting a population-level approach rather than evaluating isolated eligibility criteria. The proposed method focuses on underrepresented patient subgroups, particularly those with pre-existing conditions, with applications in oncology, specifically in relapsed or refractory multiple myeloma (RRMM). Clinically relevant subpopulations and associated safety outcomes in RRMM were identified in collaboration with clinical expert. Leveraging real-world data, we assessed the risk of safety events associated with whether a patient had or did not have a specific baseline condition (e.g., renal impairment, cardiac dysfunction, etc.). These analyses were conducted separately for anti-CD38 and standard-of-care (SoC) treatments. Inverse probability of treatment weighting (IPTW) was applied to balance baseline characteristics between patient cohorts who met versus did not meet each baseline condition. IPTW-adjusted Kaplan-Meier curves and weighted Cox proportional hazards models were used to evaluate associations between key baseline conditions and the risk of safety events, expressed as hazard ratios.

resultsOur findings indicate that patients with RRMM and renal impairment face significantly increased risks of severe renal events but do not exhibit significantly elevated risks of severe hematologic events or infections. Patients with baseline cardiac dysfunction are at higher risk of both infections and cardiovascular events, with an additional increased risk of severe renal events observed in the SoC cohort. Furthermore, patients with more than two prior lines of therapy exhibited an increased risk of severe hematological events in the anti-CD38 cohort. In the SoC cohort, patients with more than two prior lines of therapy demonstrated a higher risk of infections and cardiovascular events compared with those who had received two or fewer prior lines.

conclusionThese results provide descriptive and adjusted real-world estimates of the association between key baseline clinical conditions and the risk of safety event among patients with RRMM and may help inform clinical trial eligibility criteria. By characterizing safety outcomes in populations often underrepresented in clinical trials, this analysis offers contextual evidence to support more inclusive trial designs, while acknowledging the inherent limitations of observational data.