Introduction

In April 2024, the U.S. FDA’s Oncologic Drugs Advisory Committee (ODAC) unanimously (12–0) voted to accept minimal residual disease (MRD) negativity as a primary endpoint in multiple myeloma (MM) clinical trials seeking accelerated approval. This marks a regulatory shift, aiming to speed up the availability of new treatments. The decision stems from robust evidence, including two meta-analyses demonstrating a strong correlation between MRD negativity and improved PFS outcomes.

Publication Summary

With treatment regimens for MM becoming increasingly effective and complex, MRD testing offers a faster and more precise way to compare novel drugs and combinations. The FDA’s new guidance enables the design of randomized controlled trials (RCTs) using MRD as the primary endpoint in early treatment settings, bypassing limitations of single-arm, dose-intensive studies.

However, there are several important caveats:

  1. Sensitivity, sample quality, and methodology impact MRD test reliability. For example, flow cytometry needs to be processed quickly, typically within 48 hours, and bone marrow-based testing result accuracy can vary due to the patchy nature of myeloma and hemodilution.
  2. MRD negativity in the bone marrow does not provide a full picture. The authors anticipate technology, such as mass spectrometry (EasyM), will help bridge the gap in accurately understanding disease burden in patients, particularly in complete response (CR) or stringent CR stage when higher sensitivity is needed to detect any MRD, as well as decrease the need for invasive bone marrow sampling.
  3. Single time-point negativity is insufficient and sustained MRD negativity and kinetics is what clinical trials and clinicians should aim for as we work towards a cure.
  4. MRD negativity is a proven prognostic marker of progression free survival (PFS) and overall survival (OS), but needs to be placed in clinical context.
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Conclusions

MRD testing is now a validated potential regulatory endpoint for accelerated approval in MM, a change that may expedite novel therapy development and improve patient access. Blood-based MRD tests (EasyM) provide non-invasive testing that can be done more frequently to better understand M-protein kinetics and, as a result, offer a fast and more precise way to evaluate the effects of novel drugs.

Authors

Kumar, A. D., Chung, A., & Chari, A. (2025). Minimal residual disease as a primary endpoint in multiple myeloma: Implications for clinical trials and everyday clinical practice. The Hematologist, 22(1). https://doi.org/10.1182/hem.v22.1.202511

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