Researcher Critiques FDA Minimal Residual Disease Guidance

FDA’s draft guidance endorsing minimal residual disease (MRD) as a potential basis for accelerated drug approvals in multiple myeloma marks a watershed moment for the field, according to leading myeloma researcher C. Ola Landgren.

In an interview with Targeted Oncology, Landgren said the agency’s draft document reflects nearly two decades of research aimed at establishing MRD negativity as a reliable surrogate for long-term clinical outcomes such as progression-free survival (PFS). The guidance follows a unanimous 12-0 vote in April 2024 by the Oncology Drug Advisory Committee endorsing MRD as an acceptable endpoint for accelerated approval in multiple myeloma.

MRD refers to the presence of residual cancer cells below the threshold of conventional detection methods. As treatments for multiple myeloma have become more effective, traditional trial endpoints such as overall response rate (ORR) and even complete response (CR) have approached ceiling effects, making it increasingly difficult to demonstrate incremental benefit within practical study sizes and timelines.

“In newly diagnosed patients, roughly 95% achieve an overall response,” Landgren said. “If your control arm is already at 95%, there’s very little room to show improvement without enrolling enormous numbers of patients.”

The draft guidance outlines how MRD negativity — measured with validated, highly sensitive assays — may support accelerated approval, provided it correlates with PFS. Overall survival (OS) data, while valuable, are not required at the time of accelerated approval but remain critical confirmatory endpoints.

The document also clarifies that both single-arm and randomized trials may be used. Under one pathway, sponsors could pursue accelerated approval based on MRD findings from a single-arm study, followed by confirmatory randomized data. Alternatively, a randomized study could incorporate MRD as an early readout, with PFS maturing later to support full approval.

Landgren said the flexibility is particularly important in relapsed or refractory settings, where standard-of-care comparators evolve rapidly and can complicate trial design.

While praising the guidance as “very well written,” Landgren said certain areas could benefit from clarification. One issue is the recommended timing for MRD assessment. During ODAC deliberations, investigators were asked to evaluate MRD at 9 or 12 months from randomization (±3 months). However, newer, more potent therapies — including CAR T-cell therapies and bispecific antibodies — can induce MRD negativity much earlier.

The draft guidance uses language such as “for example” when referencing these time frames, suggesting some flexibility. Landgren argued that the document could more explicitly acknowledge that shorter or longer assessment windows may be appropriate depending on therapeutic potency.

Another concern is that the guidance also discusses CR as a possible endpoint. But Landgren cautioned that CR may soon face the same limitations as ORR. “In some settings, 80% or more of patients achieve CR,” he said. “Improving from 80% to 90% still requires very large trials.” He suggested MRD is a more pragmatic and discriminating metric, though he acknowledged that as therapies improve further, even MRD negativity rates may approach saturation. In that scenario, MRD could transition from an accelerated approval endpoint to a basis for full approval.

With more than 200,000 people living with multiple myeloma in the United States and no established cure, Landgren said the guidance could accelerate access to innovative therapies, particularly in newly diagnosed patients where long-term outcomes are most favorable. He also suggested the framework may serve as a template for other malignancies.