Association of Minimal Residual Disease With Superior Survival Outcomes in Patients With Multiple Myeloma: A Meta-analysis

Abstract

Importance: Numerous studies have evaluated the prognostic value of minimal residual disease (MRD) in patients with multiple myeloma (MM). Most studies were small and varied in terms of patient population, treatment, and MRD assessment methods.

Objective: To evaluate the utility of MRD detection in patients with newly diagnosed MM.

Data sources: A Medline search was conducted for articles published in English between January 1990 and January 2016.

Study selection: Eligible studies reported MRD status and progression-free survival (PFS) or overall survival (OS) in 20 or more patients following treatment. Among 405 articles identified, 21 met the initial eligibility criteria and were included in the analysis.

Data extraction and synthesis: Information on patient characteristics, treatment, MRD assessment, and outcomes were extracted using a standard form.

Main outcomes and measures: The impact of MRD status on PFS and OS was assessed by pooling data from relevant trials. Data were adjusted to allow for different proportions of patients with MRD in different studies, and analyzed using the Peto method. Forest plots were created based on Cox model analysis. Other prespecified research questions were addressed qualitatively.

Results: Fourteen studies (n = 1273) provided data on the impact of MRD on PFS, and 12 studies (n = 1100) on OS. Results were reported specifically in patients who had achieved conventional complete response (CR) in 5 studies for PFS (n = 574) and 6 studies for OS (n = 616). An MRD-negative status was associated with significantly better PFS overall (hazard ratio [HR], 0.41; 95% CI, 0.36-0.48; P < .001) and in studies specifically looking at CR patients (HR, 0.44; 95% CI, 0.34-0.56; P < .001). Overall survival was also favorable in MRD-negative patients overall (HR, 0.57; 95% CI, 0.46-0.71; P < .001) and in CR patients (HR, 0.47; 95% CI, 0.33-0.67; P < .001). Tests of heterogeneity found no significant differences among the studies for PFS and OS.

Conclusions and relevance: Minimal residual disease-negative status after treatment for newly diagnosed MM is associated with long-term survival. These findings provide quantitative evidence to support the integration of MRD assessment as an end point in clinical trials of MM.

Conflict of interest statement

Conflicts of Interest Disclosure

N.M.: Celgene, Takeda, Janssen, and Merck – consultancy, advisory committee membership.

K.A.: Celgene, Millennium, Gilead – consultancy

H.A.-L.: Celgene, Takeda – consultancy, advisory committee membership.

A.C.R.: Janssen – research funding; Gilead – research funding, consultancy, honoraria; Celgene, Roche, Abbvie, Genzyme, GSK – honoraria; BD biosciences – other remuneration.

R.O.: Celgene – consultancy, honoraria, research funding; Janssen – consultancy; Takeda-honoraria

A.T., P.S.: Celgene – employment and equity ownership.

J.A.C.: Celgene – research funding.

A.G.: Excerpta Medica – employment.

W.G.: Celgene – consultancy; Janssen – honoraria.

M.K.S.: no conflicts of interest.

Figures

Figure 1

Article identification and selection. AlloSCT, allogeneic stem cell transplantation; MRD, minimal residual disease; RRMM, relapsed/refractory multiple myeloma.

Figure 2

Overall effect of MRD status on PFS (A) and OS (B), indicating that MRD-negative patients had better outcomes. Tests for heterogeneity indicated no significant differences between the studies for both PFS and OS. Kaplan-Meier curves for PFS (C) and OS (D); data were adjusted to account for the different proportions of patients in each study being MRD-positive and MRD-negative. The sizes of the Forest plot squares represent the weighting of that trial in the meta-analysis, specifically the inverse variance of the Cox model estimate, and the horizontal lines represent the 95% CIs. CI, confidence interval; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival.

Figure 3

In CR patients, effect of MRD status on PFS (A) and OS (B), indicating that MRD-negative patients had better outcomes. Tests for heterogeneity indicated no significant differences between the studies for both PFS and OS. Kaplan-Meier curves for PFS (C) and OS (D); data were adjusted to account for the different proportions of patients in each study being MRD-positive and MRD-negative. The sizes of the Forest plot squares represent the weighting of that trial in the meta-analysis, specifically the inverse variance of the Cox model estimate, and the horizontal lines represent the 95% confidence intervals. CI, confidence interval; CR, complete response; MRD, minimal residual disease; OS, overall survival; PFS, progression-free survival.