Navigating MRD as an End Point in Hematologic Malignancies With Rahul Banerjee, MD, FACP, and Nicholas Richardson, DO, MPH

What Is MRD and What Does “FDA-Cleared” Really Mean?

As Dr. Richardson noted, “MRD has been incredibly impactful in the world of multiple myeloma and also other disease settings.” He defined MRD succinctly: “Ultimately, we’re talking about the ability to measure residual tumor cells in a patient with cancer.” In hematologic malignancies, this is performed through flow cytometry–based platforms or molecular-based platforms.

Dr. Richardson then addressed a common clinical misconception: the difference between “FDA-approved” and “FDA-cleared.” “When we think about medical devices, the FDA regulates them based on risk to ensure the safety and the effectiveness of the device that you’re talking about,” he explained. High‑risk devices such as heart valves require a pre-market approval and are therefore FDA-approved devices.

By contrast, MRD assays like ClonoSeq are considered moderate-risk devices. “When we talk about MRD, and we’re going to talk about ClonoSeq, it is an FDA-cleared device for MRD in patients with acute lymphoblastic leukemia (ALL), multiple myeloma, and chronic lymphocytic leukemia (CLL),” Dr. Richardson said. “That ‘FDA-cleared’ statement means that the FDA has evaluated the data with ClonoSeq to ensure that it is accurate and reliable to measure MRD.”

Is MRD a True Surrogate End Point?

Clinicians often treat MRD negativity—ideally sustained—as a stand-in for deeper outcomes such as progression-free survival (PFS) and even overall survival (OS). Dr. Richardson emphasized that the FDA uses a strict definition of surrogacy: “When you talk about a surrogate end point, that means that the surrogate is a direct correlation to the ultimate or desired clinical end point—meaning the effect that you have on MRD directly translates to the effect that you would have on PFS and OS.”

He referenced the Prentice criteria, calling them “a rigorous set of criteria to meet that goal.” Using data presented at the April 2024 ODAC, he noted that in a little over 11,000 patients with multiple myeloma, MRD did not actually meet the criteria for being a surrogate end point. Importantly, the same is true for more familiar end points: “PFS, if you think about that as an early end point, does not meet the criteria as a surrogate for overall survival.” Instead, MRD functions as a “candidate surrogate” or intermediate clinical end point. At a trial level, MRD showed a moderate to strong correlation only with PFS in newly diagnosed, transplant-ineligible myeloma, underscoring both its promise and its limitations.

What Did the 2024 ODAC Decide on MRD?

The 2024 ODAC on MRD in multiple myeloma was unusual in that it focused on a general topic rather than on a specific product. “ODAC is a group of peers assembled to give advice to the FDA team,” Dr. Richardson explained. “However, it is advisory, so it is not binding. But I will say that the input from the ODAC holds a lot of weight within the FDA.”

In this case, the ODAC voted unanimously that available data were sufficient for MRD to support future accelerated approvals in myeloma. “The accelerated approval comes into play because MRD didn’t meet the criteria as essentially a true surrogate,” he said. The ODAC outcome therefore supports MRD as a basis for accelerated approval, while recognizing the need for confirmatory outcome data.

How Should Trialists and Sponsors Design MRD-Driven Studies?

Dr. Richardson highlighted key lessons from myeloma for future MRD- or ctDNA-based end points in other cancers. “The International Myeloma Working Group (IMWG) took a really important step in that they identified what the clinical threshold would be for patients with multiple myeloma, and they included 10⁻⁵ as the clinically relevant clinical threshold.” This, he said, “standardized the clinical threshold is across an entire community” and ensured that “the analytical validation of that assay was appropriate to inform the standardized clinical threshold.”

That standardization allowed the FDA to be “assay-agnostic” across flow, polymerase chain reaction (PCR), and next-generation sequencing (NGS) platforms, as long as each could reliably reach 10⁻⁵. He argued that similar, proactive efforts in CLL and other malignancies are critical: “There are some certain steps you can take to ensure that you have informative, interpretable data that’s being generated across products, across trials, which is important when you think about the totality of data that’s going to be needed at the end of the day.”

For oncology clinicians, the message is to recognize MRD as a powerful, but not yet definitive, regulatory endpoint and to advocate for standardized, prospective MRD integration in trials.

Key Takeaways

• Flow or molecular MRD platforms are used to measure residual tumor cells in patients with cancer.
• ClonoSeq is an FDA-cleared device, meaning the FDA has determined it is accurate and reliable to measure MRD in ALL, myeloma, and CLL; this is distinct from FDA-approved for high-risk devices.
• MRD has not met Prentice criteria as a true surrogate for OS; it currently serves as a candidate or intermediate end point with disease- and setting-specific correlations.
• ODAC recommendations on MRD support MRD as a basis for accelerated approval in myeloma.
• Disease-wide standardization of thresholds (such as 10⁻⁵ in myeloma) and prospective trial planning enable assay-agnostic, interpretable MRD data that can support regulatory decisions and clinical care.

About the Speakers

Rahul Banerjee, MD, FACP, (Twitter/X: @RahulBanerjeeMD) is an Assistant Professor at the Fred Hutchinson Cancer Center and at the University of Washington in Seattle, Washington, USA. His clinical interests are in multiple myeloma and CAR T therapy. He is a member of the International Myeloma Working Group and has published over 100 peer-reviewed publications with an emphasis on improving the experiences of patients as they undergo treatment for multiple myeloma.

Nicholas Richardson, DO, MPH, is a Hematologist-Oncologist and the Vice President of Clinical Development at Precision for Medicine. Previously, he was Deputy Director for the Division of Hematologic Malignancies 2 at the FDA for nine years. In his current role, he partners with life science companies on the clinical development of their drugs, biologics, and cell and gene therapies. Dr. Richardson has extensive expertise in the development of CAR T-cell therapies, bispecifics, and T-cell engagers, and in the evolving regulatory landscape for hematologic malignancies.