EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical end point for multiple myeloma

Abstract

Estimating progression-free survival (PFS) and overall survival superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier end point surrogates that are predictive of long-term clinical benefit. Minimal residual disease (MRD)-negativity is a common intermediate end point that has shown prognostic value for clinical benefit in MM. This meta-analysis was based on the US Food and Drug Administration guidance for considerations for a meta-analysis of MRD as a clinical end point and evaluates MRD-negativity as an early end point reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD-negativity as an end point in patients with MM, with follow-up of ≥6 months following an a priori-defined time point of 12 ± 3 months after randomization. Eight newly diagnosed MM studies evaluating 4907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv, 0.67 (95% confidence interval [CI], 0.43-0.91) and R2copula 0.84 (0.64 to >0.99) at the 12-month time point. The individual-level association between 12-month MRD-negativity and PFS resulted in a global odds ratio (OR) of 4.02 (95% CI, 2.57-5.46). For relapse/refractory MM, there were 4 studies included, and the individual-level association between 12-month MRD-negativity and PFS resulted in a global OR of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical end point reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby, expedite the availability of new drugs to patients with MM.

Graphical abstract

Figure 1.

PRISMA flowchart of the systematic literature review search strategy and article selection. The literature review was conducted in adherence to PRISMA guidelines. Medline and EMBASE databases were searched for articles published in English up to 8 June 2019; there was no date limit on the indexed database searches. Details of the search strategy were performed as follows: medical subject heading (MeSH) terms for MM were “MM” and “neoplasm, residual.” Non-MeSH search terms were “Kahler disease” (or “Kahler’s disease” or “myelomatosis” or “plasma cell myeloma”) and/or “MRD.” Selected congress abstracts published between 2016 and 2019, including additional literature, were manually reviewed. Bibliographies of systematic literature review articles on MM published between 2014 and 2019 were reviewed manually to identify additional potentially relevant publications. Additional sources were used for validation, including studies identified in public assessment reports published by the European Medicines Agency and the FDA. PICOS (Population, interventions, comparisons, outcomes, and study design) criteria were used to define eligibility. Patients could have received any type of therapy except allogeneic stem cell transplantation. Studies with PFS or OS data that could not be extracted or reconstructed were excluded. Studies with patients who did not have a primary diagnosis of MM were also excluded, as were those with MRD measured only in peripheral blood or assessed only by positron emission tomography–computed tomography scanning. Two independent investigators selected the articles for potential inclusion. RCTs and observational studies that reported PFS or OS rates stratified by MRD status in patients with MM following therapy were eligible for inclusion (supplemental Table 1). The methodological quality of the studies was assessed using the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) reporting recommendations. A manual search was conducted to identify any updated publications on selected studies. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2.

Correlations with MRD negativity. (A) Correlation between treatment effect on 12-month MRD-negativity and treatment effect on PFS scaled by sample size: all-NDMM population. All-NDMM combines TE and TIE patients. Study 2.1 was not included in the primary analysis due to >20% of patients being assigned a value of missing for the primary end point definition based on MRD. This study was included in sensitivity analyses. (B) Forest plot of treatment effect on MRD and PFS.