Increasing Trends of Minimal Residual Disease Measurement in Trials Focusing on Multiple Myeloma Treatment: A Systematic Analysis of Clinical Research Design From 2014 to 2025

ABSTRACT Minimal residual disease (MRD) is a central biomarker in multiple myeloma (MM), offering unprecedented sensitivity for evaluating treatment efficacy and serving as a potential surrogate endpoint. We conducted a comprehensive analysis of clinical trials registered on ClinicalTrials.gov between 2014 and 2025. Interventional trials or observational studies investigating therapeutic interventions were included. Data on therapy response, MRD outcomes, measurement, and their role as primary, secondary, or adaptive endpoints were extracted. A total of 1336 studies met inclusion criteria. Among interventional trials, 86.4% included therapy response and 30.9% MRD as an outcome. Trials assessing MRD increased steadily from 6.7% in 2014 to 56.8% in 2025. Almost 50% of trials with recruiting (46.0%) or not yet recruiting (46.8%) status had an MRD outcome. MRD served as a primary outcome in 28.4% of trials with MRD assessment and guided therapeutic decisions in 7.5%. Most studies used next‐generation flow or sequencing at a 10 −5 threshold, though reporting heterogeneity persisted. MRD integration in trials has expanded substantially, reflecting its clinical and regulatory importance. Still, there is a need for coordinated evidence generation, standardization, and alignment with evolving EMA and HTA requirements. Future research should integrate patient experience data and emerging non‐invasive MRD technologies to enhance clinical relevance and policy acceptance.