FDA issues draft guidance on MRD and complete response as primary endpoints for accelerated multiple myeloma drug approvals

The FDA has issued a draft guidance recommending that minimal residual disease (MRD) and complete response (CR) serve as the primary endpoints for accelerating the approval of drugs and biologics for multiple myeloma (MM). Released on January 20, 2026, the document reflects how regulatory thinking has shifted and moved away from traditional assessments such as overall response rate (ORR) and toward more sensitive measurements of treatment efficacy in an era of sophisticated therapies. This change could help patients with this challenging blood cancer get access to new treatments sooner.

MM, which is caused by cancerous plasma cells in the bone marrow, affects roughly 35,000 new patients in the U.S. each year. Even while treatments such as CAR-T cell therapy and bispecific antibodies have advanced care, there remains no cure.

In the past, accelerated approvals in MM were based on ORR and length of response. However, recent trials generally show ORRs of over 90% in newly diagnosed cases and 60% to 70% in relapsed or refractory patients, making ORR less useful as a way to tell the difference.

The FDA's guidance suggests MRD negative and CR can be used as substitutes for clinical benefit, potentially speeding up development by focusing on deeper molecular responses instead of long-term survival statistics, including progression-free survival or overall survival.

The recommendation defines MRD as the negative rate measured in bone marrow samples from individuals who have reached CR using flow cytometry or sequencing methods. MRD negativity must be established at a sensitivity level of at least one tumor cell per 100,000 normal cells, with other thresholds requiring robust justification.

According to the 2016 International Myeloma Working Group standards, CR includes both conventional CR and strict CR. This means that there is no detectable monoclonal protein in serum and urine, there are no soft tissue plasmacytomas, and there are fewer than 5% plasma cells in bone marrow.

Evaluations must take place at predetermined intervals, specifically at nine or 12 months, or within a three-month period following the confirmation of CR. Sustained MRD negative or imaging-based evaluations should only be used as secondary or exploratory objectives because there isn't enough supporting data.

The FDA prioritizes randomized controlled studies for testing MRD and CR due to the safety data provided that can be compared and lets progression-free survival and overall survival be looked at again. While single-arm trials are still acceptable, the guidance notes they aren't the best option, especially for combination regimens, where sponsors must demonstrate the contribution of each component. Trials should enroll patients with measurable disease, employ independent review committees for CR assessments and collect bone marrow aspirates to reduce bias.

Sponsors are expected to send the FDA precise analysis plans and consider missing MRD data as if it were not there. Assays should also have verified sensitivity, accuracy, precision and detection limits. FDA consultation with oncology or biologics divisions is recommended. For CR endpoints, the overall CR rates should be evaluated with enough follow-up to assess durability.

The FDA's Oncologic Drugs Advisory Committee unanimously voted in April 2024 to support MRD as an accelerated approval objective. This was based on meta-analyses that showed that MRD negative was linked to better progression-free survival.

For drug companies, the approach could speed up approvals in both frontline and relapsed settings, benefitting the development of new drugs such as CAR-T treatments. MRD test makers may see this as a positive change as they expect more people to use the tests for blood cancers.

However, accelerated approvals require confirmatory trials, preferably initiated prior to approval, to validate benefits, with overall survival as a secondary aim, if not primary. Some of the problems include ensuring assay accuracy, dealing with biases in patient selection in high-risk groups and making sure trials are rigorous to prevent missing safety issues. The FDA is accepting comments on the draft guidance through March 23, 2026, giving stakeholders an opportunity to provide input before recommendations are finalized.