MRD as an early endpoint in myeloma and other hematologic malignancies: Implication for ongoing and future study designs.

Abstract

Advances in therapy have substantially improved survival across hematologic malignancies. Therefore, traditional clinical trial endpoints such as overall survival (OS) and progression-free survival (PFS) require long follow-up times delaying continued therapeutic advancement. Minimal (or measurable) residual disease (MRD) has emerged as a highly sensitive biomarker of treatment response particularly in multiple myeloma (MM). In 2024, the U.S. Food and Drug Administration (FDA) recognized MRD-negative complete responses in patients with MM as an early endpoint reasonably likely to predict clinical benefit, enabling its use to support accelerated approval for MM therapies-marking the first such acceptance in a hematologic malignancy. This review examines the scientific and regulatory pathway that led to this milestone. We summarize the extensive collaborative efforts, including large meta-analyses and regulatory engagement, that established MRD's prognostic validity. The article further explores the evolving role of MRD across other hematologic malignancies, using acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and acute myeloid leukemia (AML) as examples, highlighting disease-specific challenges to broader regulatory adoption. Finally, we discuss innovative clinical trial designs utilizing MRD that may accelerate drug development and personalize therapy. The experience in MM provides a roadmap for integrating MRD into future regulatory and clinical trial paradigms across hematologic oncology.