MRD and Complete Response End Points: New Guidance for Multiple Myeloma Trials With Rahul Banerjee, MD, FACP, and Nicholas Richardson, DO, MPH

In early 2026, the oncology community reached a significant milestone with the release of the FDA’s draft guidance regarding measurable residual disease (MRD) negativity as a clinical end point in multiple myeloma. This development follows years of debate over how to transition from legacy response criteria to more sensitive, bone-marrow-based molecular assessments. In this interview, Dr. Rahul Banerjee, Assistant Professor at Fred Hutchinson Cancer Center, sat down with Dr. Nicholas Richardson, Vice President of Clinical Development at Precision for Medicine and a former Deputy Director at the FDA, to discuss the regulatory and clinical implications of this new framework, providing a roadmap for clinicians navigating the rapidly shifting landscape of myeloma clinical trials and drug approvals. 

View additional MRD insights from Dr. Richardson and Dr. Banerjee here.

What Does the FDA Draft Guidance Mean in Practice? 

Dr. Banerjee opened the discussion by addressing the weight of "draft" guidance and how it influences the field before becoming final. Dr. Richardson clarified that while these documents are not legally binding, they are highly influential indicators of the agency's trajectory. "Guidance that comes out from the FDA is not binding, but they represent the FDA's current thinking on either current policy or a drug development topic," he explained. 

The "draft" designation invites the community to participate in the regulatory process. Dr. Richardson emphasized that the public comment period is far from a formality, noting that "every single comment that is submitted to the FDA for guidance is looked into, and it is vetted whether it should be incorporated into the guidance." This collaborative approach ensures that the final guidance is a "legitimate" product that has been vetted by hundreds of stakeholders across the global oncology space.

Balancing MRD With Traditional Response Criteria

A recurring point of contention in myeloma is the relationship between MRD negativity and traditional complete response (CR), which relies on the disappearance of paraproteins in the blood. Dr. Banerjee noted the "tension between conventional or legacy response criteria and the new shiny stuff." Dr. Richardson suggested that the FDA’s preference for MRD-negative CR, requiring both a traditional CR and MRD negativity, is rooted in the need for a standardized denominator. 

"Not all MRD negativity is the same," Dr. Richardson cautioned. He explained that from a regulatory lens, requiring a CR before assessing MRD "creates a more homogenous or standardized population to assess the new aspect of the end point or treatment effect." This is particularly vital when dealing with multicompartmental diseases where a patient might be MRD-negative in the bone marrow but still harbor extramedullary disease. He posed the question: "If you have MRD negativity in a patient with a partial response (PR) or even a very good partial response (VGPR), what does that mean?" By anchoring MRD to CR, regulators can more confidently isolate the treatment effect. 

Intent-to-Treat Principles

The technical execution of MRD testing in trials often leads to cherry-picked data, where only “evaluable” patients are reported. Dr. Richardson confirmed that using an evaluable population "is almost akin to a responder-only analysis," which can skew the perceived efficacy of a drug. Dr. Banerjee praised the FDA’s draft guidance for advocating for an intent-to-treat (ITT) approach.

To ensure data reflects the entire treated population, the FDA prefers including all patients in the denominator. Regarding missing data, Dr. Richardson explained that "the imputation methods that are most commonly used in this setting include that anybody who has missing MRD data is essentially imputed as a non-responder." While a conservative approach, this allows statisticians to characterize the impact of missing data and perform sensitivity analyses that strengthen the overall evidence of effectiveness. 

Co-Primary End Points and Accelerated Approvals

As trials move toward using MRD as a co-primary end point alongside progression-free survival (PFS), clinicians must understand how these "lagging" metrics interact. Dr. Richardson noted that this structure is perfectly suited for the accelerated approval program, which aims to provide earlier access to novel therapies. 

"The accelerated approval program has been leveraged widely to afford patients earlier access to these novel and effective therapies," he stated. By using a response-based metric like MRD, the FDA can grant approval while "knowing that there's a certain level of uncertainty" that must be confirmed later with mature PFS or overall survival data. He concluded that MRD "fits really, really well within the regulatory framework," offering a bridge between early biological response and long-term clinical benefit.

Key Takeaways

• FDA draft guidance represents current regulatory thinking and is shaped by extensive public and stakeholder feedback.

• Combining MRD negativity with traditional CR provides a more standardized and interpretable metric for drug effectiveness.

• Intent-to-treat (ITT) analysis is the gold standard for MRD reporting to avoid the bias of "evaluable-only" subsets.

• Missing MRD data is typically treated as a non-response in regulatory filings to maintain a conservative and safe efficacy estimate.

• MRD serves as a powerful tool for accelerated approval, allowing faster patient access to life-saving therapies while long-term data matures. 

About the Speakers

Rahul Banerjee, MD, FACP, 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.