A Shared Compass for Patients, Clinicians, and Regulators

MILAN — The landscape of hematologic malignancies is shifting rapidly, in part due to the evolving significance of measurable (formerly “minimal”) residual disease (MRD). Once confined to the realm of research, MRD is emerging as a critical tool for clinical and regulatory decision-making. In conditions such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and multiple myeloma (MM), MRD has become more than a marker of extent of disease burden; it now informs prognosis, therapeutic response, and access to novel treatments.

“MRD is not a new concept; it has been studied for years”, Jesus San Miguel Izquierdo, MD, PhD, director of clinical and translational medicine at the University of Navarra, Pamplona, Spain, told Medscape Medical News. Thanks to technological advances, unprecedented sensitivity in detecting residual cancer cells following treatment, in other words MRD, has been achieved. “We are capable of identifying a single tumor cell among a million,” said San Miguel Izquierdo, who was awarded the 2025 EHA Lifetime Achievement Award for his lifelong work in MM.

At a multidisciplinary session here at the European Hematology Association (EHA) 2025 Annual Meeting in Milan, representatives of patient organizations, clinicians, and regulatory bodies offered insights into the expanding role of MRD. Although its utility as an indicator of treatment response is widely recognized, debates remain over standardization, regulatory implications, and its intersection with patient experience and access.

The Patient Voice: MRD as a Tool of Hope and Anxiety

Anne-Pierre Pickaert, a survivor of ALL and patient advocate, described MRD in profoundly personal terms. For many patients, MRD is both a beacon and a burden. “It’s like a needle in a haystack,” she explained, noting that the absence of detectable cancer cells does not always equate to the absence of disease, and that uncertainty can be emotionally taxing.

The terminology shift from “minimal” to “measurable” residual disease may have technical sense, but it can be unsettling for patients. “Minimal” is often interpreted as benign or reassuring, whereas “measurable” conveys clinical precision but may also amplify anxiety. Conversely, “minimal” can offer false reassurance, underestimating actual risk.

There are also disparities in how MRD is communicated and understood across different hematologic diseases. For patients with ALL or AML, MRD status can dictate eligibility for transplants, trials, or access to novel therapies. In contrast, patients with chronic lymphocytic leukemia or lymphoma may be less familiar with the concept, reflecting its inconsistent use in routine care. Advocacy networks face challenges in delivering cohesive education across this diverse landscape.

Pickaert also used the term “MRD-xiety,” likening it to the “scanxiety” experienced by patients with solid tumors awaiting imaging results. As MRD often determines treatment direction, it carries substantial emotional weight. Yet most patients remain unaware of the regulatory frameworks that shape access to MRD-guided interventions. “We just want access,” she said, be it through compassionate use, early access programs, or full reimbursement.

Clinician Perspective: A Shift in Therapeutic Strategy

Nicola Gökbuget, MD, head of the study center, department of hematology/oncology, University Cancer Center, Frankfurt, Germany, highlighted how MRD is transforming clinical strategy. Presenting an ALL case, she emphasized the paradigm shift from hematologic to molecular decision-making. “Historically, we acted on clinical relapse. Today, persistent or re-emerging MRD — as a molecular failure — can prompt therapeutic changes.”

This proactive model is influencing clinical trial designs and enabling more personalized approaches, such as targeting residual disease before transplant. In contrast, classical strategies relied on hematologic response and salvage therapy after hematologic progression.

Still, the clinical utility of MRD depends on standardization. Clinicians need consensus definitions for response categories — complete molecular remission, intermediate response, molecular failure — as well as harmonized testing modalities and timepoints. Gökbuget stressed that the value of MRD risks being undermined without unified standards. Coordinated efforts from academic groups and industry partners will be essential.

The Regulatory View: Is Surrogacy the Right Goal?

Pierre Démolis, MD, PhD, chair of the Oncology Working Party and co-chair of the Scientific Advice Working Party at the European Medicines Agency, discussed the nuanced regulatory stance on MRD.

Although MRD is a powerful indicator of response, it is not yet a validated surrogate endpoint. Surrogacy, in regulatory terms, requires consistent, reproducible correlation with overall survival across various contexts; something MRD has not fully achieved.

Still, Démolis advocates for MRD as a “response trigger” in adaptive designs, transplant decisions, and early treatment assessments. “Let’s stop pretending surrogacy is required to make MRD useful,” he said. “It’s like objective response rate or complete hematologic response; we’ve used such endpoints for decades.”

He clarified the distinction between activity and efficacy: activity refers to pharmacodynamic effects (eg, tumor shrinkage, MRD negativity), while efficacy denotes clinical benefit (eg, overall survival, progression-free survival). Activity-based endpoints such as MRD are already used in single-arm trials, particularly when randomized data are impractical. However, MRD should not replace overall survival as the final endpoint. “It can be used in conditional settings, provided final efficacy outcomes confirm its relevance,” he added.

Survey Shows Divergence in Attitudes

Anna Smit, a PhD candidate at Erasmus MC Cancer Institute in Rotterdam, the Netherlands, presented preliminary findings from a joint EHA-International Myeloma Society survey on the role of MRD in MM trials. Among 389 healthcare professionals and 40 regulators surveyed, most supported MRD negativity as a primary endpoint, regardless of transplant eligibility.

Nearly all respondents emphasized the need for global standardization. Yet variation in techniques and sensitivities remains a major barrier.

Smit noted that in April 2024, the Oncologic Drugs Advisory Committee of the US Food and Drug Administration unanimously supported MRD-negative complete response as an endpoint to justify accelerated approval in MM. Europe, however, has not yet agreed to this and continues to monitor the field. Démolis confirmed ongoing global regulatory discussions on different topics, including MRD, highlighting monthly exchanges among agencies to share and possibly align perspectives.
 

Patient-Centered Medicine Remains Paramount

Quality of life (QoL) was also discussed during the session as another important aspect of the patient-centered approach to hematologic malignancies. For Pickaert, QoL is a non-negotiable endpoint: “Patients want survival, but not at any cost.” Démolis echoed this view: “If you prolong life by a month but destroy QoL, is that meaningful?”

Gökbuget acknowledged the practical difficulties of collecting QoL data, especially in acutely ill populations, but emphasized that such hurdles are not insurmountable. “Even when patients are unwell, someone can help complete the questionnaire,” Pickaert said.

Integrating QoL into MRD-based strategies could ensure that treatments extend not just life but also well-being. “As regulators, we must prioritize QoL in our decisions,” Démolis said.

San Miguel Izquierdo reinforced this message in a comment to Medscape Medical News. “Looking at MRD allows for early intervention,” he said, implicitly linking early intervention to better QoL. Although some clinicians worry about overtreatment, the risk of undertreatment is often far greater. “By ignoring MRD, we risk undertreating 90% of patients and overtreating 10%,” he concluded.

Pickaert, Smit, and Démolis have reported no relevant financial relationships. Gökbuget has reported advisory board participation for and speaker honoraria and travel support from Amgen, AstraZeneca, Autolus, Celgene, Clinigen, Gilead, Incyte, Jazz Pharmaceuticals, Novartis, Pfizer, Sanofi, and Servier; and institutional research support from Amgen, Clinigen, Incyte, Jazz Pharmaceuticals, Novartis, and Servier. San Miguel Izquierdo has declared participation on advisory boards and consulting services, on behalf of his institution, for AbbVie, Amgen, BMS, Celgene, GSK, Haemalogix, Janssen-Cilag, Karyopharm, MSD, Novartis, Pfizer, Takeda, Regeneron, Roche, Sanofi, Secura Bio, and Gilead-Kite. 

Cristina Ferrario is a molecular biologist and former researcher in molecular oncology at three institutes in Milan. She has a master’s degree in communication and health from the University of Milan and in cancer genetics from the University of Pavia. She has worked as a science journalist for more than 20 years.