Bridging Randomized Trial Efficacy and Real-World Effectiveness in Multiple Myeloma: Integrating Clinical Trials and...

Multiple myeloma (MM) is predominantly a disease of older adults, yet the randomized clinical trials (RCTs) that define standards of care are conducted largely in younger, fitter, and less comorbid populations. This creates a systematic mismatch between the populations generating evidence and those receiving treatment in routine practice, which can be characterized by comparing eligibility criteria, baseline characteristics, treatment exposure, and outcomes across RCTs and large real-world cohorts. Real-world data (RWD) have emerged as an essential complement to RCTs, capturing treatment effectiveness, tolerability, and patterns of care in unselected populations. Still, their use in clinical decision-making remains inconsistent. In this review, we use MM as a model to examine the divergence between trial efficacy and real-world effectiveness. Outcomes observed in RCTs are reproducible primarily in patients who resemble trial populations. In contrast, in older, frail, and comorbid patients, effectiveness is frequently attenuated by increased toxicity, reduced dose intensity, and early treatment discontinuation. We summarize how differences in comorbidity burden, frailty status, treatment intensity, and early discontinuation contribute to attenuated outcomes in routine care. Frailty, rather than chronological age alone, appears to be the principal determinant of this divergence. Despite its strong prognostic and predictive value, frailty is inconsistently measured in both RCTs and RWD, limiting the translation of evidence into practice. We highlight the prognostic and predictive value of formal frailty assessment and its current under-use in both RCTs and RWD. On this basis, we propose a pragmatic, patient-centered approach that uses trial-derived estimates of regimen efficacy together with real-world data on toxicity, dose intensity, and treatment persistence to enable systematic adaptation of regimen choice, dose, and schedule. Finally, we outline methodological priorities for future research, including standardized data elements, robust causal-inference approaches, routine incorporation of frailty, and closer alignment between RCTs and RWD. Although focused on MM, this framework has broader implications across hematologic malignancies, where bridging the gap between efficacy and effectiveness is essential to ensure that therapeutic advances translate into meaningful benefit for patients seen in everyday clinical practice.