MRD Negativity: A "Robust" Predictor of Survival Outcomes in MM

Patients with multiple myeloma (MM) who demonstrate increased minimal residual disease (MRD) negativity tend to experience greater survival outcomes. This conclusion, drawn from a recent meta-analysis published in American Journal of Hematology, suggests that MRD could be considered an effective surrogate for survival in this population.¹

MRD status cannot be detected with a microscope; it is achieved through bone marrow analysis. | image credit: © Arthur Constantine - stock.adobe.com

Novel therapeutics have transformed the treatment landscape in MM, the present authors began; however, the benefits they provide have created challenges for assessing progressive-free survival (PFS) and overall survival (OS) in patients wrangling with new diagnoses. Amid these medical breakthroughs, various trials have seen patients with MM exhibit 4- and 5-year PFS rates exceeding 84% and 63%, respectively.

“Although PFS has been widely accepted as a surrogate for OS in MM and a PFS benefit is sufficient to support a regulatory approval of a new drug indication, it may take several years to achieve data maturity with the novel quadruplet standards of care,” the authors note.

In light of this reality, identifying earlier surrogate end points that can help clinicians foresee treatment efficacy and long-term outcomes remains vital, they add, stating that the meta-analysis was designed to investigate any association between MDR negativity and patient survival.

MRD is not something that can be detected with a microscope, but instead requires the use of very sensitive assays. These assays, such as next-generation genetic sequencing, have proved useful for evaluating bone marrow. The presence of genetic mutations, or abnormal proteins if flow cytometry is used, allow clinicians to detect MRD in patients.²

Data were gathered from PubMed up to June 2024 to identify randomized controlled trials (RCTs) comparing antimyeloma treatments with placebos or standards of care—so long as MDR negativity status and PFS were reported. OS was also tracked as a secondary outcome alongside PFS for patients with MRD negative vs MRD positive status.¹

Researchers found 29 RCTs that were eligible for inclusion. Throughout all of these trials, patients with MM who were participating in the treatment arm demonstrated significantly increased chances of having an MRD negative status vs participants in the reference arms (OR, 2.88; 95% CI, 2.18-3.80; P < .05). There were 16 studies that recorded OS, and in which the researchers witnessed treatment arms experience more favorable outcomes (HR, 0.82; 95% CI, 0.72-090).

A univariate regression analysis further bolstered these findings, indicating a negative and significant correlation between MRD negativity, patient ORs and survival (PFS: β, –0.12; P = .023). A similarly significant trend was observed for patients with new diagnoses (PFS: β , −0.35; P < 0.001). Follow-up data at 1 year also suggested strong associations between maintained MRD negative status and PFS (β = –0.30; P < 0.001) and these trends continued for 2-, 3-, and 4-year follow-ups, indicating the prognostic value of MRD status and the benefits afforded to patients in treatment arms.

There were 5 studies that recorded PFS results for patients with MRD negative vs positive statuses. The meta-analysis developed sense of the pooled effect this factor had on survival, indicating that patients with MRD negative status experienced a 20% reduced risk of death compared with patients with MRD positive status (HR, 0.80; 95% CI, 0.62-1.03).

“Surrogate end points, such as PFS and MRD, provide early signs of therapy success and potentially forecast long-term results without necessitating prolonged follow-up,” the authors concluded, highlighting the validity of MRD as a “robust” predictor of patient survival as research continues advancing in MM.

References

1. Ntanasis-Stathopoulos I, Filippatos C, Nthanasis-Stathopoulos A, et al. Evaluating minimal residual disease negativity as a surrogate endpoint for treatment efficacy in multiple myeloma: a meta-analysis of randomized controlled trials. Am J Hematol. 2025. doi:10.1002/ajh.27582

2. What is minimal residual disease (MRD)? MD Anderson Cancer Center. July 15, 2020. Accessed January 9, 2025. https://www.mdanderson.org/cancerwise/what-is-minimal-residual-disease--mrd--multiple-myeloma-lymphoma-leukemia-patients.h00-159383523.html