Large Meta-Analysis Confirms Predictive Value of MRD Negativity in Myeloma

Achievement of measurable residual disease (MRD) negativity is associated with significant improvements in progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma (MM), authors reported in a meta-analysis published in Blood Advances. This association was seen in transplant-eligible and transplant-ineligible patients and those with newly diagnosed and relapsed or refractory disease.

Lead study author Nikhil Munshi, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, told ASH Clinical News that these findings indicate that MRD negativity holds strong prognostic capabilities for patients with MM and may be considered as a valid biomarker for PFS and OS in clinical care.

“MRD is becoming a very important endpoint for myeloma, and many small- and medium-sized studies have shown that MRD negativity is associated with improved survival in patients with MM,” said Dr. Munshi. What has been lacking in current research, he added, is a pooled understanding of how MRD status affects different MM settings.

In this meta-analysis, Dr. Munshi and coauthors analyzed the relationship between MRD and survival outcomes in 45 research publications, including randomized controlled trials and observational studies, that reported post-treatment rates of PFS and/or OS stratified by MRD status in patients with MM.

“There’s a separate effort to now get approval for MRD as a marker, and this meta-analysis is the first step in this direction.”

—Nikhil Munshi, MD

Forty-four of the studies contained PFS data, from a total of 8,098 patients, and 23 studies contained OS data, from a total of 4,297 patients.

Across the PFS and OS studies, 3,111 and 1,605 patients, respectively, were considered MRD-negative. The base case analysis revealed that achieving MRD negativity was associated with a significant improvement in both PFS (hazard ratio [HR] = 0.33; 95% CI 0.29-0.37; p<0.001) and OS (HR=0.45; 95% CI 0.39-0.51; p<0.001).

The authors also estimated HRs for PFS and OS across different subgroups, including disease settings, MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and measurement of MRD status before and after start of maintenance therapy. In each of these analyses, MRD negativity correlated with a higher likelihood of PFS and OS, compared with MRD positivity (TABLE 1).

For example, transplant-eligible patients with newly diagnosed MM who were MRD-negative had a median PFS of 61.0 months, compared with 24.1 months in those who were MRD-positive. In addition, the five-year PFS rates for MRD-negative and MRD-positive patients were 51% and 24%, respectively (p<0.001).

The PFS benefit with MRD negativity also was seen across cytogenetic risk groups (HR=0.45 for high-risk cytogenetics and HR=0.40 for standard-risk cytogenetics). Results from other subgroup analyses are presented in TABLE 2.

Limitations of the meta-analysis were the inclusion of studies that varied with regard to MRD detection methods, as well as the potential publication bias risk, which the investigators suggest was due to the lack of individual patient-level data.

“There’s a separate effort to now get approval for MRD as a marker, and this meta-analysis is the first step in this direction,” concluded Dr. Munshi. “The findings from this analysis do not satisfy all the needs of the FDA, but this [study] does begin to set the stage.”

Study authors report relationships with Janssen, which sponsored this trial.


Munshi NC, Avet-Loiseau H, Anderson KC, et al. Large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in multiple myeloma patients. Blood Adv. 2020;4(23):5988-5999.