CHMP Provides Positive Opinion for MRD Negativity as an End Point for Regulatory Myeloma Clinical Trials

MRD negativity in multiple myeloma |

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The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has issued positive qualification advice to the novel biomarker procedure application submitted by the i2TEAMM and the International Myeloma Foundation regarding the use of minimal residual disease (MRD)–negative complete response (CR) as an early end point for clinical trials to support conditional market approval of treatments for patients with multiple myeloma.1

The CHMP’s decision follows the April 2024 12-0 unanimous vote given by the FDA’s Oncologic Drugs Advisory Committee (ODAC) supporting the use of MRD as an end point for the accelerated approval of new treatments for patients with multiple myeloma.2

“On 5/22/2025, the CHMP met and adopted the advice to be given to the applicant,” the CHMP explained in a scientific advance letter.1 “CHMP agrees that, depending on the setting, a role for MRD-negative CR as an end point to support (conditional) approval of a compound while the obligation to demonstrate long-term benefit remains, can be envisaged. This implies that the trials should be adequately planned to demonstrate a benefit in progression-free survival [PFS] or overall survival [OS].”

During the ODAC meeting, representatives from The University of Miami’s Sylvester Comprehensive Cancer Center in Florida presented data showing high associations between 12-month MRD negativity and PFS in a population of patients with newly diagnosed multiple myeloma (n = 4907; copula global odds ratio [OR], 4.72; 95% CI, 3.53-5.90), transplant-ineligible patients (n = 3221; copula global OR, 6.15; 95% CI, 4.27-8.03), and transplant-eligible patients (n = 1686; copula global OR, 2.45; 95% CI, 1.40-3.51).3 Furthermore, investigators from The University of Miami demonstrated that MRD negativity at 12 months is prognostic for long-term OS improvements in all newly diagnosed patients (copula global OR, 4.02; 95% CI, 2.57-5.46), as well as transplant-ineligible and transplant-eligible patients (copula global OR, 4.08; 95% CI, 2.44-5.72; and copula global OR, 3.78; 95% CI, 0.78-6.78, respectively).

“I am very pleased with the CHMP opinion that MRD can be considered as a potential early end point for conditional approval of treatments in myeloma,” S. Vincent Rajkumar, MD, a consultant in the Division of Hematology in the Department of Internal Medicine, a consultant in the Division of Hematopathology in the Department of Laboratory Medicine and Pathology, and a professor of medicine at Mayo Clinic in Rochester, Minnesota; as well as Chairperson of the Board of the International Myeloma Foundation, stated in a news release.1 “This is great news for the field and is in line with a similar recommendation by ODAC in the US. We are an international organization, and we are committed to accelerating the availability of effective new treatments to [patients with] myeloma worldwide. I applaud the efforts of the i2TEAMM investigators and our entire team at the International Myeloma Foundation.”

During the ODAC meeting, the i2TEAMM presented findings showing that among patients with MRD-negative disease tested at a sensitivity of 10–5, all those who were newly diagnosed (n = 3061), transplant-ineligible (n = 2235), or relapsed/refractory (n = 1378) had greater odds of being alive and progression-free beyond 9 months (OR, 8.27; 95% CI, 6.53-10.01; OR, 9.80; 95% CI, 5.14-14.46; and OR, 8.24; 95% CI, 4.41-12.07, respectively).3 This outcome was also observed beyond 12 months in all patients with MRD-negative disease who were newly diagnosed (n = 3009), transplant ineligible (n = 2281), or relapsed/refractory (n = 863; OR, 9.15; 95% CI, 7.27-11.03; OR, 11.95; 95% CI, 7.32-16.58; and OR, 16.24; 95% CI, 5.77-26.71, respectively).

“The acceptance of the International Myeloma Foundation/i2TEAMM application by the [EMA’s] CHMP represents one of the most significant milestones in our collective mission to accelerate innovation and cure in multiple myeloma,” Nikhil Munshi, MD, director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center, the Kraft Family Chair, director of Multiple Myeloma Immune Effector Cell Therapy, and a senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts; a professor of medicine at Harvard Medical School; a member of the i2TEAMM Executive Committee; and a member of the Advisory Board and the Board of Directors at the International Myeloma Foundation, added in the news release.1 “Recognizing MRD as a valid early end point brings us one step closer to delivering more timely, effective therapies to patients. This scientific advancement reflects the strength of global collaboration and data-driven progress in the field.”

References

1. The International Myeloma Foundation proudly announces EMA-CHMP positive qualification advice to i2TEAMM novel biomarker procedure application on the use of MRDnegCR as an intermediate early endpoint for conditional market approval in myeloma clinical trials. News release. International Myeloma Foundation. July 2, 2025. Accessed July 2, 2025. https://www.myeloma.org/news-events/multiple-myeloma-news/imf-proudly-announces-ema-chmp-positive-qualification-advice-i2teamm-novel-biomarker-procedure
2. April 12, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/watch?v=pooME9gMaL0
3. Oncologic Drugs Advisory Committee (ODAC) Meeting. Combined FDA and Applicants ODAC Briefing Document. Accessed July 2, 2025. https://www.fda.gov/media/177652/download