Myeloma Experience Paves the Way for MRD in Trial Design and Regulatory Approval

The rapidly evolving treatment field for multiple myeloma brings with it the ultimate benefit of longer lifespans for patients, but it also brings dilemmas, including extended wait times to data readout, regulatory application, and eventual access to new therapies, according to Sonja Zweegman, MD, PhD, of Amsterdam UMC in the Netherlands. That’s why measurable residual disease (MRD) holds such promise as a key surrogate end point in myeloma and other hematological malignancies, where it can help solve the trial design troubles that have plagued the field in recent years.

As Zweegman explained in the Presidential Session of the European Hematology Association 2026 Congress, the discovery of new standards of care means that trials are often designed with comparator arms that, by the time of data maturation, no longer represent the best regimen with which to compare an investigational agent. When treatments can’t be compared head-to-head, an incremental cost-effectiveness ratio (ICER) is difficult to calculate, Zweegman said, and “the lack of certainty about ICER may be one of the reasons for the very long average time from registration to availability.”

To solve this problem, additional randomized controlled studies are needed to evaluate unanswered questions like comparative effectiveness and treatment optimization, but there needs to be a sustainable funding pathway for these academia-sponsored trials that may not receive industry funding, Zweegman said. Similarly, prospective adaptive trials incorporating a revised control arm and repeated randomization would provide better evidence but remain cost-prohibitive.

Stakeholder Perspectives on MRD in Myeloma

Instead, more researchers are turning to MRD as a surrogate end point, particularly in myeloma, Zweegman said, because it is easy to measure and prognostic for survival at the patient level, with a moderate but encouraging correlation with progression-free survival (PFS) at the trial level. It also gives investigators a clear improvement to aim for, as research has found that a 20% increase in MRD negativity rate translates to a clinically relevant superior PFS with an HR less than 0.6.¹

“Patients’ opinions are not just desired but required,” Zweegman emphasized. Although more evidence is needed on their feelings toward use of MRD negativity as an end point, prior data reveal a patient preference toward valuing PFS over the risks of toxicity from treatment.²

Regulators are more skeptical of MRD, with unpublished data showing they are more likely than health care providers to disagree that the advantages of making decisions based on MRD outweigh the unknowns surrounding the long-term benefits and risks. Zweegman noted the uncertainty in the European regulatory context around using MRD data to support approval and confirming benefits in longer-term postmarketing follow-ups, as the FDA has begun to do.³

Debunking MRD Misconceptions, and What’s Next

A concern is that aiming for MRD could occur at the cost of patient quality of life, but Zweegman highlighted early data showing that an MRD-negative arm reported no significant differences in adverse events or quality of life compared with those who did not achieve MRD negativity. The measurement of quality of life has room to improve across the board, she noted, given its heterogenous definitions and haphazard reporting across myeloma trials: “There’s a need for harmonizing the methodology and reporting of quality-of-life analysis in multiple myeloma studies.”

Another objection is that earlier data readouts enabled by MRD negativity will fail to capture late-appearing adverse effects. Zweegman argued that most neurotoxicity events will appear within the window using 12-month MRD as an end point, but infections and second primary malignancies will require longer follow-up, which could be achieved via global real-world data registries.

“MRD is a key surrogate end point being accepted by the FDA for accelerated market access already,” Zweegman said, “but trials should remain powered for PFS and followed for [overall survival] and quality of life.” She called for further investigation of the ideal prognostic timepoint for assessment, as well as the potential for MRD using peripheral blood instead of bone marrow to align with patient preferences.

References

1. Paiva B, Zherniakova A, Nuñez-Córdoba JM, et al. Impact of treatment effect on MRD and PFS: an aggregate data analysis from randomized clinical trials in multiple myeloma. Blood Adv. 2024;8(1):219-223. doi:10.1182/bloodadvances.2023010821
2. Postmus D, Richard S, Bere N, et al. Individual trade-offs between possible benefits and risks of cancer treatments: results from a stated preference study with patients with multiple myeloma. Oncologist. 2018;23(1):44-51. doi:10.1634/theoncologist.2017-0257
3. Shaw ML. FDA draft guidance proposes CR, MRD to accelerate MM drug approval. Am J Manag Care. 2026;32(Spec. No. 2):SP91.