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i2TEAMM provides a comprehensive presentation based on results of an extensive retrospective meta-analysis review; FDA now actively engaged in reviewing implementation strategies.
 

On Friday, April 12, the U.S. Food and Drug Administration (FDA) held an Oncologic Drugs Advisory Committee (ODAC) meeting to discuss “the use of minimal residual disease (MRD) as an endpoint in multiple myeloma clinical trials, including considerations regarding timing of assessment, patient populations, and trial design for future studies that intend to use MRD to support accelerated approval of a new product or a new indication.”

An advisory committee “provides independent expert advice to the FDA on broad scientific topics or on certain products to help the agency make sound decisions based on the available science. Advisory committees make non-binding recommendations to the FDA, which generally follows the recommendations but is not legally bound to do so,” according to the FDA.

The International Myeloma Foundation (IMF) and collaborative research group i2TEAMM (International Independent Team for Endpoint Approval of Myeloma MRD) were at front and center of the proceedings as one of the applicants, along with Sylvester Comprehensive Cancer Center of the University of Miami, headed by Dr. Carl Ola Landgren.

i2TEAMM representatives in attendance include yours truly as the IMF’s Chief Scientific Officer; Bruno Paiva, PhD (CIMA Laboratory Diagnostics, University of Navarra—Pamplona, Spain); Qian Shi, PhD (Mayo Clinic—Rochester, MN); and Kenneth C. Anderson, MD (Dana-Farber Cancer Institute and Harvard Medical School—Boston, MA).

Other i2TEAMM members who were unable to attend were Prof. Jesús San Miguel, MD, PhD (Clinica Universidad de Navarra—Pamplona, Spain) and Nikhil Munshi, MD (Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute—Boston, MA), who was not permitted to participate as a government employee.

What is the Purpose of the ODAC Meeting?

For this advisory meeting, the FDA convened the ODAC “to discuss the adequacy of available data to support the use of minimal residual disease (MRD) as an endpoint to support accelerated approval of new therapies for patients with multiple myeloma.”

The FDA briefing document notes that  “while overall response rate (ORR) has generally supported accelerated approval of MM therapies, recent advances, and improved understanding of the impact of minimal residual disease on long-term outcomes has increased interest in evaluating MRD as an endpoint to support drug approval for patients with multiple myeloma.”

“Recent improvements in technologies to detect the presence of malignant cells at orders of magnitude below the limit of conventional ORR has allowed an assessment of MRD in MM. MRD is a measure of tumor burden assessed in the bone marrow sample. MRD as a biomarker has multiple regulatory uses including for response assessments and as a prognostic marker.”

“The International Myeloma Working Group (IMWG) has established uniform response criteria for MRD for use in MM. MRD has been included as an exploratory endpoint and secondary endpoint to assess response to therapies in MM clinical trials and when the data is robust, MRD data has been included in the prescribing information.” 

“Several studies and meta-analyses have reported the prognostic value of MRD in MM and the achievement of MRD negativity has been associated with depth of clinical response and prolongation of PFS and OS. These analyses have increased interest in evaluating MRD as an endpoint to support approval in MM clinical trials,” according to the FDA briefing document.

The i2TEAMM Presentation

During the i2TEAMM presentation, I was honored to do the introduction; Dr. Paiva presented on the Need for MRD Assessment; Dr. Shi discussed Meta-Analyses and Key Results; and lastly, Dr. Anderson summarized and concluded the presentation.

Introduction

For the introduction, I emphasized the importance of Deep Response and why it matters. If you refer to the slide below, using a diagram, I illustrated how much deeper the response is at 10-5 MRD level (1 out of 100,000) vs ORR (50 percent response) and CR (100 percent response by conventional immunofixation/IFE). I also illustrated how using MRD as an endpoint at 9 or 12 months has a major impact on patients since decisions about treatment impact can be made so much sooner through timely drug or combination approvals.

depth of response

 


 

 

 

 

 

 

 

 

 

 

 

The Need for MRD Assessment

In his presentation, Dr. Bruno Paiva summarized the need for MRD assessment. He noted how MRD testing is now available using two state-of-the-art technologies: Next-Generation Sequencing (NGS) and Next-Generation Flow Cytometry (NGF) which give equivalent accurate results and can be performed for essentially all patients in clinical trials.

MRD testing has been shown to be prognostic in both frontline and relapse settings. MRD test results have affirmed PFS results that are used as basis for multiple FDA approvals in phase 3 trials.

The i2TEAMM Retrospective Meta-Analysis

Objectives
The initial objective of the study was “to validate MRD as a full surrogate endpoint of PFS in MM clinical trials using individual patient data (IPD) from a large collection of randomized clinical trials. Unfortunately, the trial-level datasets were insufficient to support MRD as a full surrogate.
 
Based on the FDA’s feedback, the i2TEAMM revised its objective to state: “To evaluate if current available data can support MRD as an Early Endpoint that is reasonably likely to predict clinical benefit in future MM clinical trials through a two-level meta-analytic evaluation: primary evaluation is based on individual-patient-level correlation by Global Odds Ratio (OR); and a supplemental evaluation through a trial-level correlation.”
 
Key Results
Based on i2TEAMM’s data presented by Dr. Shi, “high individual-patient-level correlation supports consideration of early endpoint for accelerated approval,” with “consistent high individual-patient-level correlations providing strong evidence that 9 months MRD neg-CR rate at 10-5 threshold reasonably likely predicts clinical benefit of PFS in newly diagnosed transplant-eligible (NDTE), newly diagnosed transplant-ineligible  (NDTinE) and relapsed/refractory MM (RRMM) populations.”
 
Similar results were obtained using a 12-month MRD neg-CR endpoint. At both 9 and 12 months, correlations were strong for both PFS and OS and in all three disease settings: NDTE, NDTinE and RRMM. Both the Global Odds Ratio and Landmark analyses confirmed evidence of clinical benefit.
 
“MRD neg-CR rate classified at 10-5 threshold at 9 and 12 months is reasonably likely to predict clinical benefit in NDTE, NDTinE, and RRMM settings.”
 

Conclusion

Dr. Anderson summarized the presentation with the following key points:

  • There is a clear unmet need for an early endpoint to accurately assess deep response.
  • MRD testing using a 10-5 cut-off sensitivity level meets this need.

i2TEAMM concluded that “based on the results observed in this meta-analysis of multiple large, randomized studies, there is sufficient evidence to support use of MRD as an endpoint for accelerated approval, with PFS maintained as a long-term endpoint for confirmation of clinical benefit,” as stated in the FDA briefing document.

ODAC Panel Discussion

After the oral testimonials, applicants and committee members engaged in thorough discussions on the following:

  1. The adequacy of the available data to support the use of MRD as an AA endpoint in MM.
  2. Whether the available data supports the use of MRD as an endpoint in the different MM settings (NDMM, RRMM)
  3. The acceptability of the timepoints for MRD assessment:
  • 9 months, 12 months, MRD negative CR at any time
  • Requirement for assessment of durability 

Durability of MRD Negativity: How is it Assessed?

i2TEAMM indicated that follow-up testing is strongly recommended for the next trials. In the MRD response criteria (2006 IMWG Uniform Response Criteria and 2016 IMWG Consensus Criteria for Response and MRD Assessment in MM ) sustained MRD negativity is an important category and ODAC confirmed its importance.

What About Safety?

If achieving MRD negativity is the focus, will safety be compromised? Both the i2TEAMM and ODAC members agreed close early monitoring plus longer-term survival follow-up are essential to tracking safety concerns. The BELLINI Trial was used as reference, where more MRD negativity was achieved but more toxicity-related deaths also occurred.


What About Trial Designs to Provide the Best Answers?

Can trials be single-armed or is randomization needed? How can crossovers be handled such that patients can be offered the best treatment options in trials? Multiple options and opportunities were discussed by the panel.


Can the MRD-negative CR Endpoint be Immediately Applied to New Therapies Such as CAR T and/or Bispecific Antibodies and Other Immune or New MOA Trials?

Using strong data in the relapsed setting plus new CAR T and TCE data, the i2TEAMM affirmed that MRD-negative CR can be immediately applied. ODAC members indicated that careful trial design and appropriate monitoring of new therapies can be assessed to make the application of MRD-negative CR valid and usable. The new endpoint was accepted across all settings— NDTE, NDTinE, and RRMM. This means that MRD can be used in the early assessment of new drugs.
 

ODAC Unanimously Votes in Favor of MRD Testing (12-0)

At the end of the ODAC advisory meeting, the panelists decided on the question: “Does the evidence support the use of MRD as an accelerated approval endpoint in MM Trials?” and voted unanimously in favor of MRD testing as an early endpoint in MM trials (12-0).

This was a historic unanimous vote that accepts MRD-negative CR as a reliable early endpoint. All ODAC panelists agreed that the new endpoint has clear data support. Committee members then focused on asking the FDA questions regarding implications.

Please note that the ODAC’s recommendations are non-binding, and that it is still up to the FDA to make the final decision.

The Bottom Line

The ODAC’s unanimous vote is historic— a turning point in myeloma clinical trials, as the bar has been set higher with deep responses as the endpoint of trials and with MRD-negative CR as the new standard for CR. This moves us steadily towards much more improved outcomes and a potential cure.

Expectations for new therapies and combinations are that they can and will produce durable long-term benefits with acceptable and hopefully, excellent QoL along the way. There is a pivot from controlling myeloma to attempting to achieve a cure.

If approved by the FDA for clinical use, MRD testing as an early endpoint for accelerated approvals in MM clinical trials would considerably expedite the development of FDA-approved myeloma drugs and therapies and bring them into the market sooner than later.

I am truly grateful for being able to work with the members of the i2TEAMM on this groundbreaking retrospective meta-analysis for MRD testing. This is nearly 10 years of our hard work and dedication paying off and coming into fruition.

I would also like to thank Myeloma Specialist and Cellular Therapist Saad Z. Usmani, MD, MBA, FACP (Memorial Sloan Kettering Cancer Center—New York, NY); and myeloma patient and advocate Linda Huguelet for their participation during the oral testimonials.

We all came together with one voice, echoing this immediate need for all myeloma patients, and the myeloma community at large.

Now, we await the FDA’s final decision. The IMF will keep you posted on the outcome.

In case you missed it, you can still view the ODAC proceedings via a recorded YouTube video. 


Image of Dr. Brian G.M. DurieProfessor of Medicine, Hematologist/Oncologist, and Honoree MD at the University of Brussels, Dr. Brian G.M. Durie is Chairman Emeritus and Chief Scientific Officer of the IMF. Dr. Durie is also the Chairman of the International Myeloma Working Group (IMWG)—a consortium of more than 250 myeloma experts from around the world—and leads the IMF’s Black Swan Research Initiative® (BSRI). 

 

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