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

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.

Persistent bone marrow minimal residual disease as a “high‐risk” disease feature in multiple myeloma

“…The current study indicates for the first time to our knowledge that the outcome of NDMM patients with persistent BM MRD positivity at all assessments resembles that of primary refractory disease; in both circumstances, sequential intensive therapies failed to eradicate residual MRD clone(s). 8,9 Notably, at diagnosis the distribution of However, the prognosis of MRD positive patients is worse in the setting of higher stage of the disease (ISS stage) and high-risk disease (GEP 70) consistent with previous studies. 6 Recent reports indicate that phenotypic and genomic features of MRD tumor cells show the presence of therapy-induced clonal selection with overexpression of adhesion molecules, integrins and chemokine receptors conferring a survival advantage in the BM microenvironment.…”

Making clinical decisions based on measurable residual disease improves the outcome in multiple myeloma

“…The assessment of bone marrow measurable residual disease (MRD) has consistently shown a significant prognostic value in patients with multiple myeloma (MM), with a benefit in survival outcomes associated with MRD negativity surpassing the value of complete response [ 1 , 2 ]. Next-generation sequencing and Euroflow on bone marrow reach higher sensitivity than standard flow, increasing the predictive potential [ 3 , 4 ].…”

“…Next-generation sequencing and Euroflow on bone marrow reach higher sensitivity than standard flow, increasing the predictive potential [ 3 , 4 ]. Thus, MRD was included in the consensus criteria for response [ 5 ] and its role as a surrogate marker for survival outcomes is under consideration [ 1 , 6 ]. Preliminary studies suggest that MRD dynamics could demonstrate greater prognostic value than just the MRD status at a single time point [ 7 , 8 ].…”

Propensity-score matched analysis of the efficacy of maintenance/continuous therapy in newly diagnosed patients with multiple myeloma: a multicenter retrospective collaborative study of the Japanese Society of Myeloma

“…In addition, with regard to the cytogenetic abnormalities and R-ISS stage, the bene t of maintenance therapy in PFS (Perrot et al, 2018). A large meta-analysis has con rmed the signi cance of MRD negativity as the most relevant surrogate marker not only for PFS but also for OS (Munshi et al, 2020). Taken together, these results suggest that the long-term outcome depends on the susceptibility of MM cells to any treatment.…”