Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis

Abstract

Driven by access to better drugs, on average, newly diagnosed multiple myeloma patients have over 10 years overall survival. Using modern combination therapies-with or without the addition of high-dose melphalan and autologous stem cell transplantation-up to 80% of patients reach a complete response. As a logical and necessary step forward, clinical studies have explored strategies to detect minimal residual disease (MRD) and its correlation with clinical outcomes. In this context, MRD has been proposed as a regulatory end point for drug approval in newly diagnosed multiple myeloma. To better define the role of MRD negativity in relation to clinical outcomes, we undertook a meta-analysis including published clinical trials of newly diagnosed multiple myeloma patients. We applied a random effects model which weighted studies using the inverse-variance method. Studies were combined on the scale of the logarithm of the hazard ratio (HR) and the corresponding s.d. We found that MRD negativity (versus positivity) was associated with better PFS (HR=0.35; 95% confidence interval (CI) 0.27-0.46; P<0.001) and overall survival (HR=0.48; 95% CI 0.33-0.70; P<0.001). Our results show that MRD negativity is a strong predictor of clinical outcomes, supportive of MRD becoming a regulatory end point for drug approval in newly diagnosed multiple myeloma.

FIGURE 1. SEARCH CRITERIA FOR SYSTEMATIC REVIEW

Footnote: On December 22, 2015; we applied a comprehensive MEDLINE (via PubMed), EMBASE, and Cochrane’s Central Register of Controlled Trials (CENTRAL) search strategy. For details see Methods Section. Upon careful review of the 20 identified studies^{–, –}, 4 studies were excluded because they reported on allogeneic transplantation^–; 7 were excluded because they did not evaluate the association between MRD status and progression-free survival and/or overall survival^–; 4 were excluded because they analyzed the same cohort of patients (duplicates)^–; and 1 was excluded because the timing of MRD analysis was not specified.

FIGURE 2. MRD STATUS AND CLINICAL OUTCOMES IN NEWLY DIAGNOSED MULTIPLE MYELOMA

*A higher hazard ratio indicates increased risk for each survival endpoint. Footnote: Four studies with information on MRD status and hazards ratios for progression-free survival were included in the final analysis^–; three studies had information on overall survival^– (however, one study had no deaths during the original follow-up window) so two studies provided hazards ratios for overall survival.