FDA’s Accelerated Approval Pathway: MRD as an Intermediate Endpoint in Multiple Myeloma Trials

On April 12, the FDA Oncologic Drugs Advisory Committee, or ODAC, met with leading multiple myeloma key opinion leaders (KOLs) and other stakeholders to discuss the topic of minimal residual disease, or MRD, as a clinical endpoint. Two groups, the Sylvester Comprehensive Cancer Center of Miami FL, led by Dr. Ola Landgren, and the i2TEAMM, led by Drs. Brian Durie (IMF) and Nikhil Munshi (DFCI), presented data from separate meta-analyses (meaning data from numerous previous studies that are combined to produce a summary study that is more likely to have statistically significant results) of previous clinical trials where MRD was measured at specific timepoints and then correlated to progression free survival (PFS) and overall survival (OS). These meta-analyses together involved 42 clinical trials and 21,006 patients in total.  Specifically, the question the ODAC discussed and voted on was “Does the data presented support the use of MRD as an intermediate clinical endpoint for accelerated drug approval in multiple myeloma?”

As a bit of background, the MMRF, in collaboration with Dr. Landgren and the FDA, has been supporting yearly meetings on this topic since 2014. There is a clear need for new therapies in myeloma, and with new immunotherapies currently lengthening the lives of patients and improving overall response rates (ORR), it has become more difficult to accumulate significant PFS data in trials in a reasonable timeframe, which is currently required for FDA approval; this can sometimes take up to 10 years, and many patients are unable to wait that long for new effective therapies to be approved. Using MRD measurement at a specific timepoint in a trial, 9 months and/or 12 months (+/- 3 months) after treatment is initiated, may provide assessment of sustained MRD, which is a hallmark of deep response to the clinical regimen.

After careful presentation of the data by both groups and an extended discussion with the FDA of the take-aways from the data, the ODAC panel voted 12-0 in favor of the use of MRD as an intermediate endpoint to support accelerated approval. What this means:

• Study sponsors can use MRD as the primary endpoint when they are seeking accelerated approval (which refers to new drug approval in serious conditions, such as myeloma, based on “surrogate endpoints”, which is an indirect indicator of improvement in the illness or disease). MRD must be measured at specific timepoints (9 or 12 months) as both the FDA and ODAC concluded that sustained MRD negativity was associated with a positive clinical outcome. This could significantly shorten the time to approval for new agents.
• The MRD testing used can be either multiparametric flow cytometry (MPFC) or next-generation sequencing (NGS), with a minimum sensitivity of being able to detect down to 1 myeloma cell in 100,000 normal cells (10⁵)
• Both PFS and OS will continue to be measured for all trials, but accelerated approval based on MRD negativity data could occur before PFS data are mature
• If a newly approved agent does not provide extended PFS/OS despite achieving MRD negativity, the FDA has the option of removing the agent from the market; this has happened in myeloma and in other cancers where response rate was the intermediate endpoint and the subsequent confirmatory trials did not confirm the initial results
• MRD results should not be used in clinical decision-making at this time, ie. for restarting, changing, or discontinuing therapy, until appropriate approved guidelines are in place; however, the MMRF is committed to leading efforts to generate and analyze data that would answer the question of whether sustained MRD negativity could be used as a tool to make clinical decisions (eg, whether to stop therapy)
• The trials analyzed in the meta-analyses did not include the latest approved immunotherapies, so it will be important to analyze the data from more recent trials to look for any discrepancies and confirm sustained MRD negativity in important and meaningful regardless of the treatment used.

MRD testing may become more commonplace, but for now is mainly available only in major academic medical centers. For more information about this topic or anything else myeloma-related, please contact our patient navigators at 1-888-841-6673, Mon-Fri 9AM – 7PM ET, or by email at [email protected].