OBJECTIVES : There is a need for surrogate endpoints that can predict PFS/OS outcomes and MRD has emerged in recent years as a clinical biomarker of importance in hematologic malignancies. This work seeks to assess the status of MRD as a clinical endpoint in MM and its acceptance in current and future decision making.

METHODS : A targeted review was conducted for the level of usage/acceptability of MRD as an endpoint in MM from multiple perspectives. The review included articles in PubMed, clinical trials, the FDA and EMA, HTA bodies, and clinical societies. The search strategy combined terms for MRD and multiple myeloma and the selected resources were manually reviewed.

RESULTS : MRD and MM is the topic in 885 articles in PubMed and the number is increasing yearly. A total of 141 MM clinical trials include MRD as an endpoint. In 2013, MRD first appeared as an endpoint and has since become commonplace as a secondary endpoint. Both the FDA and EMA have published guidelines on the use of MRD in MM clinical trials, signaling the need for standardization of practices, although neither body supports the validation of MRD as a surrogate for PFS/OS. The HTA bodies remain skeptical. Out of approximately 80 recent HTAs for MM, only 10% reported and discussed MRD data and it was never the basis for decision making. In fact, the G-BA, HAS, and NICE were all critical of MRD as a non-validated surrogate endpoint. Finally, clinical societies are in favor of MRD as a clinical endpoint and continue to push for its acceptance by regulatory bodies.

CONCLUSIONS : While substantial academic/clinical support exists for the use of MRD as an endpoint in MM clinical trials, regulators and HTA bodies are skeptical, a situation unlikely to change until there is enough evidence for MRD to be validated as a surrogate for PFS/OS.