In a “Historic” Moment, FDA Committee Rules on a Faster Way to Approve Therapies for Multiple Myeloma, Based on Sylvester Research 

Sylvester Comprehensive Cancer Center physician-scientist C. Ola Landgren in his white coat.
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  • An advisory committee at the U.S. Food and Drug Administration voted “yes” on a major shift in how the agency evaluates new treatments for multiple myeloma, after a presentation by Sylvester researchers on Friday, April 12.  
  • They presented their assessment of a newer way to evaluate treatments through measuring “minimal residual disease.”  
  • If the FDA adopts this new endpoint, patients will gain quicker access to new therapies, said Sylvester physician Dr. C. Ola Landgren. Dr. Landgren led the assessment, called the “EVIDENCE meta-analysis.”

Easing the pathway to approval for new cancer treatments is a priority for 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. 

Dr. Landgren and his colleagues have worked for years with U.S. regulatory authorities to assess how to improve the evaluation of new treatments for multiple myeloma, the second-most common type of blood cancer. 

The researchers’ efforts reached a critical point Friday, April 12, at a meeting with the U.S. Food and Drug Administration. There, they made the case that a clinical trial endpoint called minimal residual disease (MRD) is superior to current requirements for accelerated drug approval, a common regulatory pathway.  

The meeting occurred before the Oncology Drugs Advisory Committee, which advises the FDA on drug approvals and policy. The committee voted 12-0 in favor of adopting the new endpoint. 

The agency often accepts the recommendations of its expert committees, and if it rules positively on this change, the result will be faster approval of new treatments for multiple myeloma. 

“This is a historic moment for the myeloma field,” said Dr. Landgren. The proposed change “will give patients access to new therapies, many years sooner than with the current endpoints.”

The proposal also has broader implications for other types of cancer in the longer-term. It would “open the field for other diseases to move in the same direction, and it could give cancer patients access to therapy many years sooner, in a much broader context beyond myeloma,” said Dr. Landgren.

In support of the shift, Dr. Landgren presented data from research he has led for more than 15 years evaluating MRD in multiple myeloma, the EVIDENCE (Evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma) meta-analysis.

“The research and evidence presented by Dr. Landgren was impactful, positive, clear and convincing,” said Stephen Nimer, M.D., Sylvester director, Oscar de La Renta Endowed Chair in Cancer Research, and executive dean for research at the Miller School. “The vote by ODAC supporting the use of minimal residual disease to approve new multiple myeloma treatments will greatly speed up the development of new drugs for myeloma and help the thousands of patients with myeloma receive optimal therapy,”

Changes in how the FDA assesses multiple myeloma drugs are badly needed, said Dr. Landgren. More than a dozen new therapies for the disease have entered the clinic in the last two decades, dramatically extending the average survival rate for affected individuals. However, approximately 40% of patients still succumb to the disease within five years.  

“Today’s ODAC positive vote (12-0 in favor) for MRD as an early endpoint for accelerated approval of new multiple myeloma drugs is fantastic news for patients diagnosed with multiple myeloma. With MRD as a new endpoint, it will give patients access to new therapies much faster! This is exactly what patients need and want,” said Dr. Landgren. “It is a milestone in the field of multiple myeloma and will set the stage for the development of novel therapies for other cancers.”

The FDA Gauntlet 

A host of oncology treatments go through the FDA’s accelerated approval pathway, an expedited process for new drugs and biologics for serious or life-threatening diseases.  

Treatments taking this pathway must show an advantage over available therapies based on a biomarker or other endpoint that is likely to predict clinical benefit. Sometimes, drugs may have to clear a post-marketing study to confirm a benefit in the clinic, such as showing improved overall survival.

Drs. C. Ola Landgren and Sean Devlin at an FDA committee meeting
Dr. C. Ola Landgren (left) and Dr. Sean Devlin at the FDA meeting in Washington, D.C.

For years, the accepted endpoint for myeloma for the accelerated pathway has been a measurement called the overall response rate (ORR), based on a blood biomarker and other data.  

An increasing number of newly diagnosed multiple myeloma patients are meeting that endpoint — 90 to 99% with one recently adopted regimen, said Dr. Landgren.  

Although the overall response rates are high, new drugs are still “absolutely” needed, said Dr. Landgren. Meeting the ORR endpoint requires only a 50% reduction in disease, he explains.  

“Patients with residual disease will inevitably suffer from relapse and refractoriness,” said Dr. Landgren. “In multiple myeloma, there is an unmet need until we have a cure.”  

The Need for a New Endpoint 

With so many patients meeting the ORR endpoint, showing that a new drug is superior to existing therapies in clinical trials has become increasingly difficult.  

To show a statistically meaningful benefit, researchers have to wait for study data to mature on the clinical outcome of progression-free survival, said Dr. Landgren. It could take 10 years or longer for a new drug to clear the bar.  

“It is no longer possible to develop new therapies for patients with newly diagnosed multiple myeloma, with ORR in the accelerated approval pathway,” said Dr. Landgren. “There is an urgent need for a new objective early endpoint which can replace ORR.”  

Also joining the meeting was Jenny Ahlstrom, a patient advocate who has lived with multiple myeloma since her diagnosis at age 43, 10 years ago.  

“Patients are living longer, and that’s a blessing. But it’s also sort of a curse when it comes to clinical trials or drug development because now we have to wait longer to get results, especially for newly diagnosed patients,” said Ahlstrom, who is CEO and founder of the HealthTree Foundation, which provides support to blood cancer patients.  

“How do we maintain the pace of innovation?” asked Ahlstrom. 

Researchers have long focused on minimal residual disease (MRD) as a newer endpoint.  

A Focus on Minimal Residual Disease 

Techniques that measure MRD can detect tumor cells in the blood or bone marrow with a sensitivity down to one in a million cells, including a DNA-based test cleared by the FDA for the market in 2018. Clinical trials for multiple myeloma now routinely test for MRD, and doctors use the measurement to guide treatment decisions.  

MRD is such a sensitive readout of disease that researchers can start to see differences in responses between drug regimens quickly, within months. Studies have shown that MRD negativity correlates with clinical improvements, such as overall survival and progression-free survival. 

In 2009, Dr. Landgren helped bring together the FDA, the National Heart, Lung and Blood Institute and the National Cancer Institute, where he was then chief of the Multiple Myeloma Section. The agencies launched an initiative to assess MRD as a measurement of the disease.  

Since then, Dr. Landgren and his colleagues have regularly conducted research assessing the link between MRD and clinical outcomes. Last year, they completed the EVIDENCE meta-analysis, assessing more than 1,616 high-quality studies involving more than 8,000 multiple myeloma patients, conducted using criteria pre-approved by the FDA.  

The meta-analysis was conducted in collaboration with researchers at other institutions, including Memorial Sloan Kettering Cancer Center, where Dr. Landgren was chief of the Myeloma Service after leaving the NCI and before joining Sylvester. Sloan Kettering associate attending biostatistician Sean Devlin, Ph.D., led the statistical evaluation. 

“We have worked relentlessly on this for 15 years, and we have had continuous FDA feedback throughout the process,” said Dr. Landgren. “This is a very big undertaking.”  

Bolstering their case is a separate analysis led by the International Myeloma Foundation and Mayo Clinic researchers, which was also presented at the FDA meeting, said Dr. Landgren.  

“The results from these two independent studies are consistent and supportive of each other, which is a major strength,” said Dr. Landgren, who joined Sylvester in 2020. 

Seeking a Cure   

From the start, Dr. Landgren’s aim at Sylvester has been to build a world-class program in multiple myeloma.

“Our mission is driven by the unmet medical needs of patients diagnosed with myeloma,” said Dr. Landgren, who is also the leader of Sylvester’s Experimental Therapeutics Program.  

“He comes at things with an expectation that we can cure this disease,” said Ahlstrom of Dr. Landgren. “He has a sense of urgency.”

Ultimately, other types of cancer may benefit from a similar approach to assessing disease through MRD or comparable measurements. The new ruling shines the light on the path forward.  

The efforts of Dr. Landgren and his colleagues on MRD in multiple myeloma also may help pave the way with regulatory authorities for other blood cancers that use the same measurement.  

Dr. Landgren hosts an annual meeting that brings together researchers, regulators and other stakeholders who are assessing MRD in multiple myeloma, including the HealthTree Foundation and other patient groups. The next meeting takes place virtually on May 9.  

“It’s great that we have all these new drugs, but we are not done yet,” said Ahlstrom. “I don’t just want five years more. I want decades more.”

Ahlstrom and other patients may not have long to wait for the final ruling from the FDA. The agency typically issues its decision on committee recommendations within several weeks. 

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