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FDA Asks Experts if MRD Can Be an Accelerated Approval Endpoint in Multiple Myeloma Trials


NEW YORK – The US Food and Drug Administration will convene its Oncologic Drugs Advisory Committee (ODAC) on Friday to discuss whether minimal residual disease (MRD) — a measure of the reduction of cancer cells in the body following treatment — can reliably predict whether multiple myeloma drugs will benefit patients and support their accelerated approval.

Multiple myeloma represents about 17 percent of all hematologic malignancies and accounts for 2.1 percent of all cancer deaths in the US per year. While median overall survival for newly diagnosed patients with multiple myeloma has risen from 3.5 years to more than a decade as a result of new treatments, the disease remains incurable with a five-year relative survival rate just under 60 percent.

Some of the therapies approved in the last 20 years that have helped improve outcomes for multiple myeloma patients include proteosome pathway inhibitors like Millennium/Takeda and Janssen's Velcade (bortezomib) and Amgen's Kyprolis (carfilzomib); thalidomide derivatives such as Bristol Myers Squibb's Revlimid (lenalidomide) and Pomalyst (pomalidomide); antibody therapies like Janssen's Darzalex (daratumumab) and Talvey (talquetamab); and CAR T-cell therapies like BMS's Abecma (idecabtagene vicleucel) and Janssen's Carvykti (ciltacabtagene autoleucel).

At this Friday's ODAC meeting, experts will not focus on any specific multiple myeloma treatment, but the FDA will ask the committee to consider whether the totality of data on MRD as an endpoint can support accelerated approval of multiple myeloma drugs in general. The agency can approve treatments on an accelerated clip based on a drug's positive impact on a surrogate endpoint, but that surrogate endpoint must be validated to be reasonably likely to predict clinical benefit. The FDA is essentially interested in hearing from its advisory committee members as to whether they consider MRD to be a surrogate endpoint in this setting based on available evidence.

Historically, the FDA has approved new monotherapies and combination treatments for multiple myeloma under the regular approval pathway based on the therapy's impact on progression-free survival and an assessment of overall survival. Alternately, the agency has accepted overall response rate, including patients with partial response, supported by duration of response as surrogate endpoints for accelerated approval. However, with recent advances in technology for detecting malignant cells far below the limits of detection for conventional overall response rate assessment, MRD has emerged in multiple myeloma clinical trials as a secondary or exploratory endpoint and has been included in the prescribing information for certain multiple myeloma drugs, including Darzalex and Abecma.

In briefing documents published ahead of Friday's meeting, the FDA presented two meta-analyses conducted by researchers at the University of Miami and the International Independent Team for Endpoint Approval of Myeloma MRD (i2TEAMM), a group organized by the International Myeloma Foundation.

The meta-analysis led by C. Ola Landgren, a hematologist at the University of Miami Health System, includes patient-level data from multiple randomized, controlled Phase II and III confirmatory clinical trials in patients with newly diagnosed multiple myeloma in which MRD negativity was a primary, secondary, or exploratory endpoint. All trials used the FDA-cleared Adaptive Biotechnologies clonoSEQ 2.0 diagnostic test or multiparametric flow cytometry for MRD analysis, both of which have a sensitivity of 1 in 100,000 cells. They found that there was a strong individual-level association between achieving MRD negativity a year after initiating treatment and both progression-free and overall survival. Landgren and colleagues concluded that the data supported MRD as a prognostic marker for determining multiple myeloma patients' long-term outcomes, and that as an endpoint, MRD is likely to predict whether patients will benefit from treatment.

The i2TEAMM meta-analysis, meanwhile, included 20 randomized multiple myeloma trials for which the researchers were able to obtain patient-level data, including clinical and pathological baseline values, tumor response data, MRD data, progression and survival data, and other relevant information. The researchers included trials that tested for MRD using any validated multiparametric flow cytometry or next-generation sequencing method with a sensitivity of 1 in 10,000 cells or better.

They concluded that patients who achieve MRD negativity after a complete response to treatment have a much better long-term prognosis than those who do not, which lends support to MRD negativity as a surrogate endpoint for predicting outcomes. The i2TEAMM's analysis further showed that progression-free survival should remain as a confirmatory endpoint for proving that MRD negativity does translate to a long-term clinical benefit in Phase III trials. "Based on the results observed in this meta-analysis of multiple large, randomized studies, i2TEAMM believes there is sufficient evidence to support use of MRD as an endpoint for accelerated approval, with [progression-free survival] maintained as a long-term endpoint for confirmation of clinical benefit," the group wrote.

The FDA's reviewers generally agreed with the conclusions of both meta-analyses, noting that MRD-negative complete responses at nine or 12 months after initiating treatment was highly correlated at the individual-patient level with progression-free and overall survival in multiple myeloma settings and that MRD-negative complete responses are strong prognostic factors. However, that association did not necessarily translate to the trial level.

While the data from the meta-analyses were encouraging, the FDA's reviewers expressed concern that MRD may ultimately not predict clinical benefit with long-term follow-up. "However," the agency acknowledged that "this is a risk with the use of any early endpoint."

For example, in the Phase III BELLINI trial of AbbVie and Genentech's Venclexta (venetoclax) with Velcade and dexamethasone compared with Velcade and dexamethasone in patients with relapsed or refractory multiple myeloma, overall survival was worse in the Venclexta arm, despite improvements in progression-free survival, overall response rate, and MRD.  

Even if MRD negativity may not always translate in the long run into an overall survival benefit, the agency suggested in briefing documents that MRD could still support accelerated approval with subsequent confirmatory data from the same trial showing long-term clinical benefit. The FDA also observed that while the currently available evidence may permit use of MRD as a surrogate endpoint in newly diagnosed and relapsed or refractory multiple myeloma settings, as yet there are no data supporting its use as an accelerated approval endpoint in other settings like smoldering multiple myeloma.

The FDA also highlighted several caveats with regard to certain methods applied in the meta-analyses for its advisory committee to consider. For example, the trials in the meta-analyses focused on small molecules and monoclonal antibodies, but none included CAR T-cell therapy, which is now available for multiple myeloma patients. "It is uncertain whether any correlations observed would translate to new types of therapy," the agency wrote. "Recently published data suggests that MRD is correlated with progression-free survival after treatment with [Abecma]."

Regulators also mentioned variation between assays and MRD sensitivity measurements, and that most of the trials in the meta-analyses did not include a nine-month or 12-month MRD rate as a secondary endpoint. "Thus, it is unclear what level of missingness one might expect in a future trial where such an endpoint is a primary or key secondary endpoint," the agency added.

The questions the FDA's advisors will consider on Friday include whether the available data are adequate to support use of MRD as an accelerated approval endpoint; whether available data support MRD as an endpoint in different multiple myeloma disease settings; and what time points and durability are acceptable for MRD assessments. After discussing these points, the committee will vote on whether the evidence supports using MRD as an accelerated approval endpoint in multiple myeloma clinical trials.

The FDA is not bound to take the advice of its advisory committees, but it historically has.