The FDA's Oncologic Drugs Advisory Committee (ODAC) has recognized minimal residual disease (MRD) as an acceptable endpoint for accelerated approval of new treatments in multiple myeloma. In a unanimous vote of 12 to 0, the committee agreed that available data support the use of MRD negativity to expedite the approval process for promising therapies. This decision marks a significant step in the treatment paradigm for multiple myeloma, potentially accelerating patient access to innovative drugs.
Data Supporting MRD as an Endpoint
During the ODAC meeting, the FDA, along with representatives from the University of Miami's Sylvester Comprehensive Cancer Center and i2TEAMM, presented independent data sets from a meta-analysis of patient-level data derived from multiple clinical trials. The University of Miami's analysis revealed a strong association between 12-month MRD negativity and PFS in newly diagnosed multiple myeloma patients (n = 4907; copula global OR, 4.72; 95% CI, 3.53-5.90). Similar associations were observed in both transplant-eligible and transplant-ineligible populations.
The evaluation of the association between 12-month MRD negativity and overall survival (OS) demonstrated that MRD negativity at 12 months is prognostic of improved long-term OS in all newly diagnosed patients (copula global OR, 4.02; 95% CI, 2.57-5.46), transplant-ineligible patients (copula global OR, 4.08; 95% CI, 2.44-5.72), and transplant-eligible patients (copula global OR, 3.78; 95% CI, 0.78-6.78).
i2TEAMM also presented global odds ratio estimates regarding the measurement of individual-level associations between 9- and 12-month MRD negativity and PFS. At an MRD testing sensitivity level of 10–5, all newly diagnosed (n = 3061), transplant-ineligible (n = 2235), and relapsed/refractory (n = 1378) patients had greater odds of being alive and progression-free beyond 9 months, with respective odds ratios of 8.27 (95% CI, 6.53-10.01), 9.80 (95% CI, 5.14-14.46), and 8.24 (95% CI, 4.41-12.07).
Caveats and Considerations
Despite the positive vote, concerns were raised regarding the limitations of using MRD as a surrogate endpoint. Ravi A. Madan, MD, senior clinician at the National Cancer Institute, cautioned that while MRD meets the criteria for accelerated approval, vigilance is required to ensure that financial incentives do not compromise long-term clinical efficacy. "We talked a little bit about how that may lead to throwing the baby out with the bathwater, as financial incentives may pressure industry to hit the MRD mark or decide not to continue. On the flip side, it could raise other concerns that hitting MRD may not translate into long-term clinical efficacy. Therefore, the FDA needs to pay close attention as it always does, to safety, progression-free survival [PFS], and other relevant points like survival," Madan added.
The FDA also acknowledged several limitations in the meta-analyses, including variations in treatment types, assay standardization, and patient populations. The agency emphasized the need for continued monitoring of PFS, OS, and safety to confirm the clinical benefit of treatments approved based on MRD negativity.
Implications for Clinical Trials and Drug Development
The ODAC's decision is expected to influence the design of future clinical trials in multiple myeloma, with MRD negativity potentially serving as a primary endpoint for accelerated approval. However, i2TEAMM concluded that their analysis, while confirming the prognostic value of MRD negativity, does not support replacing PFS with an MRD-based endpoint in phase 3 trials. They stated that treatment effects on MRD at a sensitivity of 10–5 or better are 'reasonably likely' to predict treatment effects on PFS.
The University of Miami echoed this sentiment, supporting MRD as an endpoint "reasonably likely" to predict clinical benefit. This consensus suggests a balanced approach, where MRD serves as an early indicator of efficacy while longer-term endpoints like PFS and OS remain critical for confirming sustained clinical benefit.
