Significant Published Analysis Supports New “MRD” Endpoint for Multiple Myeloma

Medical illustration of multiple myeloma cells in the bloodstream
Article Summary
  • A new meta-analysis shows a tight correlation between patient clinical outcomes and a new proposed endpoint for drug approval, minimal residual disease (MRD).
  • The analysis was used to support a key FDA committee decision in favor of the new multiple myeloma endpoint.
  • Sylvester researcher C. Ola Landgren, M.D., Ph.D., led the study, a culmination of 15 years of effort.

A key committee at the U.S. Food and Drug Administration voted in April to allow a new way to evaluate drugs for multiple myeloma. The method uses an endpoint called minimal residual disease (MRD) that promises to accelerate the development of new therapies.

The unanimous 12-0 committee decision was based in large part on an analysis spearheaded by C. Ola Landgren, M.D., Ph.D., director of the Myeloma Research Institute at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. 

On May 20, the journal Blood published Dr. Landgren’s study, a deep meta-analysis of 12 phase 2 or phase 3 clinical trials.

“It shows that there is a very tight correlation between MRD and clinical outcome both in newly diagnosed and in relapsed patients,” said Dr. Landgren.

If adopted by the FDA, the committee’s recommendations will be “amazing” for patients, said Dr. Landgren. The new endpoint will enable drug approval through a special, accelerated pathway based on MRD and shave years off the process. Final, full approval would depend on longer-term data evaluating clinical outcomes like overall survival.

The FDA typically adopts its committee recommendations. A decision may come within weeks.

“It will be like switching from steam engines to jet planes,” said Dr. Landgren.

The new analysis also shows a path forward for other blood cancers and solid tumors, said Dr. Landgren. Since the committee’s decision, he has fielded calls from experts in other cancer fields asking for advice on adopting MRD as an FDA-sanctioned endpoint.

They need to collect the data to convince the FDA, said Dr. Landgren. But he is hopeful that for other types of cancer it won’t take 15 years. That’s how long it’s been since he and colleagues began investigating using MRD as a biomarker of treatment success.

“This was a very long process,” said Dr. Landgren.

The new study is called the EVIDENCE meta-analysis, shorthand for “evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma.” Its origins began at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), where Dr. Landgren was an investigator in 2009. New treatments were just coming onboard then.

“With the drugs we had at the NIH, we could achieve very deep responses in a very high proportion of patients,” he said. “And I was thinking, ‘If this continues, we will eventually have deep responses in the majority of patients. And it’s going to be very hard to develop drugs.’”

Sylvester Comprehensive Cancer Center physician-scientist C. Ola Landgren in his white coat.
Dr. C. Ola Landgren’s minimal residual disease endpoint work stretches back to 2009.

That’s because it’s hard to show an improvement over existing drugs that already yield a response. One key endpoint, overall response rate, only requires half of the tumor to shrink.

“And we were getting close to 99% of our patients having that response,” said Dr. Landgren. “It was getting very hard to develop a drug to show superiority.”

Back then, he was performing calculations in his NCI office suggesting that it would take 10 years for the data to mature on a large clinical trial. That was on top of the two years it typically takes to enroll and begin treating patients. So he and his colleagues went all in on assessing MRD as an endpoint.

He began to talk to the FDA about the data he would need. Then he began to collect it. That was a “major effort” because he had to convince multiple drug companies to share their data. During that time, technology to measure residual tumor cells in the body through MRD also improved.

The minimum sensitivity for MRD-negativity is typically one myeloma cell per 100,000 normal cells. A newer, FDA-cleared, DNA-based test can detect one in a million cells.

The EVIDENCE meta-analysis evaluated data on MRD in both newly diagnosed and relapsed/refractory patients (patients whose tumors had returned or did not respond to treatment).

The study evaluated eight clinical trials of newly diagnosed patients, covering 4,907 patients in total. The data for these patients showed a “strong association” between MRD negativity and a commonly used clinical outcome, progression-free survival. The association between MRD negativity and overall survival in this population was “moderate.”

Four clinical trials were evaluated for relapsed/refractory patients. These data showed a “strong association” between MRD and both progression-free and overall survival in these patients.

Dr. Landgren estimates that a new MRD endpoint could mean that FDA-ready data on clinical trials could emerge within three years after the start of clinical trial enrollment.

The need is huge. Despite recent therapeutic advances, 40% of patients with multiple myeloma, the second most common type of leukemia, die within five years.

“We don’t yet have a cure for the disease. We need a much faster timeline for new therapies,” said Dr. Landgren.

Dr. Landgren is the first author of the EVIDENCE analysis. Co-senior authors are:

• Maryalice Stelter-Stevenson, M.D. Ph.D., chief of flow cytometry at the National Cancer Institute

• Gerald Marti, M.D., from the National Heart, Lung and Blood Institute

• Lead statistician Sean Devlin, Ph.D., from Memorial Sloan Kettering Cancer Center

Tags: Dr. C. Ola Landgren, multiple myeloma, Sylvester Comprehensive Cancer Center