Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2020 Dec 8;4(23):5988-5999.
doi: 10.1182/bloodadvances.2020002827.

A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma

Nikhil C Munshi  1   2 , Herve Avet-Loiseau  3 , Kenneth C Anderson  1 , Paola Neri  4 , Bruno Paiva  5 , Mehmet Samur  1 , Meletios Dimopoulos  6 , Margarita Kulakova  7 , Annette Lam  8 , Mahmoud Hashim  7 , Jianming He  8 , Bart Heeg  7 , Jon Ukropec  9 , Jessica Vermeulen  9 , Sarah Cote  8 , Nizar Bahlis  4
Affiliations
Meta-Analysis

A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma

Nikhil C Munshi et al. Blood Adv. .

Abstract

The prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with multiple myeloma (MM) using a systematic literature review and meta-analysis. Medline and EMBASE databases were searched for articles published up to 8 June 2019, with no date limit on the indexed database. Clinical end points stratified by MRD status (positive or negative) were extracted, including hazard ratios (HRs) on PFS and OS, P values, and confidence intervals (CIs). HRs were estimated based on reconstructed patient-level data from published Kaplan-Meier curves. Forty-four eligible studies with PFS data from 8098 patients, and 23 studies with OS data from 4297 patients were identified to assess the association between MRD status and survival outcomes. Compared with MRD positivity, achieving MRD negativity improved PFS (HR, 0.33; 95% CI, 0.29-0.37; P < .001) and OS (HR, 0.45; 95% CI, 0.39-0.51; P < .001). MRD negativity was associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory MM), MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment premaintenance and 12 months after start of maintenance therapy. The strong prognostic value of MRD negativity and its association with favorable outcomes in various disease and treatment settings sets the stage to adopt MRD as a treatment end point, including development of therapeutic strategies. This large meta-analysis confirms the utility of MRD as a relevant surrogate for PFS and OS in MM.

PubMed Disclaimer

Conflict of interest statement

Conflict--interest disclosure: N.C.M. has received consulting fees from AbbVie, Adaptive, Amgen, Celgene, Janssen, Legend, Oncopep, and Takeda. H.A.-L. has received consulting fees, research funding, and travel and lecture fees from AbbVie, Amgen, BMS/Celgene, Janssen, Sanofi, and Takeda. K.C.A. has received consulting fees from Bristol-Myers Squibb, Celgene, Gilead, Janssen, Precision Biosciences, Sanofi-Aventis, Takeda, and Tolero. P.N. has received consulting fees, honoraria, and research funding from Amgen, Celgene, and Janssen. B.P. has received consulting fees from Celgene, Janssen, and Sanofi; was on the advisory boards and received honoraria for lectures from Adaptive, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, Sanofi, and Takeda; and received unrestricted grants from Celgene, EngMab, Sanofi, and Takeda. M.D. has received consulting fees, honoraria, and research funding from Amgen, Celgene, Janssen, and Takeda and participated in advisory boards for Sanofi-Aventis. M.K., M.H., and B.H. are employees of Ingress-Health. A.L., J.H., J.U., J.V., and S.C. are employees of Janssen. N.B. has received consulting fees and honoraria from AbbVie, Celgene, Janssen, Karyopharm, and Takeda. M.S. declares no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
PRISMA flowchart of the systematic literature review search strategy and article selection.
Figure 2.
Figure 2.
Base-case analysis of association of MRD negativity. PFS (A) and OS (B). No., number; TE, treatment eligible; TIE, treatment ineligible.
Figure 3.
Figure 3.
PFS outcomes. (A) Association of MRD negativity with PFS outcomes in patients by disease setting. (B-D) KM estimates of PFS in patients with NDMM who were transplant eligible (B), NDMM who were transplant ineligible (C), and RRMM (D).
Figure 4.
Figure 4.
OS outcomes. (A) Association of MRD negativity with OS outcomes in patients by disease setting. KM estimates of OS in patients with NDMM who were transplant eligible (B) and RRMM (C).
Figure 5.
Figure 5.
MRD sensitivity threshold. Association of MRD negativity with PFS (A) and OS (B) outcomes in various subgroups of patients with MM. aP vs MRD positive. bMRD sensitivity thresholds at 10−4, 10−5, and 10−6 were defined as 1 MM cell per 10 000, 100 000, and 1 000 000 nucleated cells, respectively. cGenetic abnormalities reported in high-risk patients in this meta-analysis were predominantly defined as the presence of t(4,14), t(14,16), and/or del(17p). dStandard risk was defined as the absence of genetic abnormalities seen in high-risk patients. eOnly includes studies with MRD sensitivity thresholds at 10−5 and 10−6; in studies including 10−4, 10−5, and 10−6 MRD sensitivity thresholds, the HR estimates for PFS and OS were 0.41 (95% CI, 0.36-0.46) and 0.49 (95% CI, 0.42-0.57), respectively. fIncludes studies that reported immunophenotypic CR, stringent CR, or near CR. gDoes not overlap with CR. hMRD assessed at 100 days post-ASCT. iMRD assessed at 12 months after start of maintenance therapy.
See this image and copyright information in PMC

References

    1. Anderson KC, Alsina M, Atanackovic D, et al. ; National Comprehensive Cancer Network . Multiple myeloma, version 2.2016: Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2015;13(11):1398-1435. - PMC - PubMed
    1. Mills JR, Barnidge DR, Dispenzieri A, Murray DL. High sensitivity blood-based M-protein detection in sCR patients with multiple myeloma. Blood Cancer J. 2017;7(8):e590. - PMC - PubMed
    1. Gay F, Cerrato C, Petrucci MT, et al. . Efficacy of carfilzomib lenalidomide dexamethasone (KRd) with or without transplantation in newly diagnosed myeloma according to risk status: results from the FORTE trial. J Clin Oncol. 2019;37(15 suppl):8002.
    1. Korde N, Roschewski M, Zingone A, et al. . Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol. 2015;1(6):746-754. - PMC - PubMed
    1. Yoroidaka T, Takamatsu H, Yamashita T, et al. . Minimal residual disease assessment using Euroflow-NGF in patients with multiple myeloma treated with a combination of carfilzomib, lenalidomide, and dexamethasone (KRD). Blood. 2019;134(suppl 1):3130.

Publication types