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Hematology From the European Perspective: MRD Negativity Emerges as Key Outcome

Enthusiasm abounded at the recent European Hematology Association 2024 Congress about whether European regulators will begin to consider minimal residual disease (MRD) as an end point.

At the European Hematology Association (EHA) 2024 Congress, held June 13-16 in Madrid, Spain, several researchers noted the growing role of minimal residual disease (MRD) as an important outcome when assessing response to treatment for hematologic malignancy and hinted that the continent’s regulators may soon heed these findings.

Microscope slides for laboratory research | Image Credit: © Kirsten D/peopleimages.com - stock.adobe.com

Minimal residual disease refers to a very small number of cancer cells detected after treatment for hematologic malignancies. | Image Credit: © Kirsten D/peopleimages.com - stock.adobe.com

In the plenary abstract session held on June 15, Thierry Facon, MD, professor of hematology, Department of Hematology at Lille University Hospital in France, presented findings from the phase 3 IMROZ study (NCT03319667) of isatuximab plus bortezomib, lenalidomide, and dexamethasone (Isa-VRd) vs VRd alone for newly diagnosed, transplant-ineligible multiple myeloma (MM).1 The results were the same as those presented at the American Society of Clinical Oncology meeting earlier in June2 and published in the New England Journal of Medicine,3 with the highlight being that Isa-VRd met its primary end point of improving progression-free survival (PFS), with a 60-month PFS rate of 63.2% in the Isa-VRd group vs 45.2% in the VRd group. However, the EHA presentation provoked questions from a different angle: the MRD negativity rates and their potential impact on European drug approval.

Facon noted that the rate of sustained MRD negativity for 1 year was almost doubled in the arm receiving isatuximab, leading plenary session cochair Konstanze Döhner, MD, professor at University Hospital of Ulm in Germany, to ask whether it’s time to change primary end points from PFS to achievement of MRD negativity. He concurred, noting that the FDA appears poised to do so for accelerated approvals following unanimous endorsement from the Oncologic Drugs Advisory Committee,4 and he expects the European Medicines Agency (EMA) to follow suit. “I cannot speak for EMA, but I anticipate that it will be the same for us in Europe, so MRD will become an end point, at least in the beginning for accelerated approval, but…we will move from PFS to MRD assessment,” he said.

Delving into the topic further, Bruno Paiva, PharmD, PhD, of the University of Navarra in Spain, presented during the plenary session on June 16 about innovative tools for disease monitoring in MM, including next-generation MRD assessment. He explained that these methods of monitoring have become very sensitive and standardized, with prediction of clinical benefit improving as sensitivity increases, which led to the FDA advisors’ consensus that MRD-negative complete response can be considered an early end point for trials to support accelerated approval.

Paiva said that we are in the midst of a uniquely exciting era of progress on myeloma therapy, with many new drugs and combination therapies emerging with impressive survival outcomes, but the downside of this progress is that “patients will have to wait for longer and longer periods for documented PFS benefits and ultimately to enjoy the new drugs and combinations. This is why we need accelerated approval based on biomarkers and surrogate end points,” including MRD negativity.

He updated the audience on best practices in MRD assessment, including that MRD trends are more informative for prognosis than a single assessment and that it’s most important to measure MRD during intensive treatment stages like induction or dose escalation, whereas peripheral residual disease and PET/CT imaging can be employed in the maintenance and observation phases. He also noted the potential to halt therapy based on MRD negativity, but some “red flags” that would lead him to continue therapy include late achievement of MRD negativity, higher International Staging System score, and a higher presence of circulating tumor cells.5,6

“There is no precision medicine without precision diagnostics,” he said.

In response to a question from the audience, Paiva emphasized that the use of MRD negativity in the drug approval process so far only applies to accelerated approval. “For a formal surrogate end point, which could replace survival outcomes, we will need to show a stronger correlation, 0.8 or higher, at the trial level between treatment effect in the 2 arms and the MRD negativity rates.”

References

1. Facon T, Dimopoulos MA, Leleu X, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). Presented at: EHA 2024 Congress; June 15, 2024; Madrid, Spain. Accessed June 20, 2024. https://library.ehaweb.org/eha/2024/eha2024-congress/422204/thierry.facon.phase.3.study.results.of.isatuximab.bortezomib.lenalidomide.and.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Ace_id%3D2552%2Amarker%3D5098%2Afeatured%3D18498

2. Facon T, Dimopoulous MA, Leleu XP, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). J Clin Oncol 2024;42(suppl 16):Abstract 7500. doi:10.1200/JCO.2024.42.16_suppl.7500

3. Facon T, Dimopoulous MA, Leleu XP, et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. Published online June 3, 2024. doi:10.1056/NEJMoa2400712

4. Durie BGM. A historic turning point: ODAC unanimously votes in favor of MRD testing as an early endpoint in myeloma clinical trials to support accelerated approvals of new treatments. International Myeloma Foundation. April 18, 2024. Accessed June 20, 2024. https://www.myeloma.org/blog/dr-duries/odac-unanimously-in-favor-mrd-testing-early-endpoint-myeloma

5. D’Agostino M, Bertuglia G, Rota-Scalabrini D, et al. Predictors of unsustained measurable residual disease negativity in patients with multiple myeloma. Blood. 2024;143(7):592-596. doi:10.1182/blood.2023022080

6. Guerrero C, Puig N, Cedena MT, et al. Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma. Blood. 2024;143(7):597-603. doi:10.1182/blood.2023022083

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