MRD Moves to Center Stage in Multiple Myeloma: Nicholas Richardson, DO, MPH

The FDA’s January draft guidance proposing minimal residual disease (MRD)-negative complete response as a primary end point to support accelerated approval in multiple myeloma has drawn significant interest from drug developers, clinicians, and patient advocates. Nicholas Richardson, DO, MPH, vice president of clinical development at Precision for Medicine and former FDA deputy director for the Division of Hematologic Malignancies, shared his perspective on the guidance’s implications.

Richardson identified calibration failures as one of the most persistent challenges in MRD assay standardization across clinical trial sites. Multiple trials across numerous drug developers attempted MRD assessments that ultimately could not be included in FDA labels, largely because sample collection issues and insufficient DNA input led to inadequate evaluations.

“Calibration failure became a big issue,” Richardson noted, stressing that assays must be analytically valid and that sponsors should proactively troubleshoot known risks. The goal is to generate MRD data that are clinically meaningful on a patient-by-patient level and robust enough for inclusion in an FDA label.

He also described the single-trial model as a potentially powerful tool when used thoughtfully. Rather than conducting a single-arm trial in a heavily pretreated population for accelerated approval, followed by a separate randomized trial to confirm benefit, a single randomized trial in an earlier treatment line, such as patients with 1 to 3 prior lines, could serve both purposes.

An early MRD-negative complete response assessment between arms could support accelerated approval, while long-term follow-up would confirm progression-free survival and overall survival. However, Richardson emphasized that sponsors must fully power this MRD assessment, prespecify a rigorous statistical analysis plan, ensure complete enrollment before the primary MRD readout, and engage proactively with the FDA throughout.

On the question of a timeline for finalizing the guidance, Richardson was candid: it is difficult to predict. The FDA reviews every public comment submitted, and the depth and substance of those responses will shape the path to a final document. He encourages all stakeholders—drug developers, patient advocates, and patients alike—to engage with draft guidance and submit comments, noting that this input will produce the strongest possible guidance.