A comprehensive meta-analysis, encompassing data from 14 studies and 1,273 patients, has confirmed that achieving minimal residual disease (MRD) negativity significantly improves both progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma (MM). The study reinforces the importance of MRD status as a prognostic marker and a potential surrogate endpoint in clinical trials.
The meta-analysis, which included studies published between January 1990 and January 2016, evaluated the impact of MRD status on PFS and OS in newly diagnosed MM (NDMM) patients following therapy. MRD was assessed using various methods, including multiparameter flow cytometry (MFC), allele-specific oligonucleotide quantitative polymerase chain reaction (ASO-qPCR), and next-generation sequencing (NGS), with a limit of detection of 0.01% or lower.
Impact on Progression-Free Survival
The analysis revealed that MRD negativity was associated with a significantly better PFS compared to MRD positivity (HR 0.41; 95% CI 0.36–0.48; P < .0001). Median PFS was 54 months for MRD-negative patients and 26 months for MRD-positive patients. This indicates that patients who achieve MRD negativity experience a considerably longer period without disease progression.
Impact on Overall Survival
Similarly, MRD negativity correlated with improved OS (HR 0.57; 95% CI 0.46–0.71; P < .0001). The median OS was 98 months for MRD-negative patients and 82 months for MRD-positive patients, demonstrating a substantial survival advantage for patients achieving MRD negativity.
MRD Status in Patients Achieving Complete Response
Even among patients who achieved conventional complete response (CR), the presence of MRD predicted shorter PFS (HR 0.44; 95% CI 0.34–0.56; P < 0.00001) and OS (HR 0.47; 95% CI 0.33–0.67; P = 0.00006). Median PFS was 56 months for MRD-negative patients and 34 months for MRD-positive patients, while median OS was 112 and 82 months, respectively.
Consistency Across Treatment Types
Importantly, the prognostic value of MRD status remained consistent regardless of the therapies used, suggesting that the predictive value of MRD status was independent of the type of treatment. This finding supports the integration of MRD assessment into the management of MM to inform treatment decisions.
Potential Applications of MRD Assessment
Assessment of MRD has several important potential applications in MM. In clinical trials, MRD assessment after initial treatment could be a useful surrogate endpoint for PFS and/or OS. In clinical practice MRD testing may aid in prognostication; help make decisions regarding subsequent treatment, especially consolidation treatment; and, in the near future, guide the type and duration of maintenance therapy.
Limitations and Future Directions
The analysis did not account for the type of MRD test used in each study, and the timing of MRD assessment varied among the studies. Future trials will need to focus on some of these questions to determine the clinical utility of MRD assessment as well as its ability to inform treatment decisions.
In conclusion, this meta-analysis provides strong evidence that MRD negativity predicts better PFS and OS in patients with MM, including those who have achieved CR. MRD status is a marker of long-term outcomes in patients with MM and should be considered a new endpoint in clinical trials and clearly has a role as a surrogate marker of OS.
