Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma

Abstract

The introduction of novel agents has led to major improvements in clinical outcomes for patients with multiple myeloma. To shorten evaluation times for new treatments, health agencies are currently examining minimal residual disease (MRD) as a surrogate end point in clinical trials. We assessed the prognostic value of MRD, measured during maintenance therapy by next-generation sequencing (NGS). MRD negativity was defined as the absence of tumor plasma cell within 1 000 000 bone marrow cells (<10^-6). Data were analyzed from a recent clinical trial that evaluated the role of transplantation in newly diagnosed myeloma patients treated with lenalidomide, bortezomib, and dexamethasone (RVD). MRD negativity was achieved at least once during maintenance in 127 patients (25%). At the start of maintenance therapy, MRD was a strong prognostic factor for both progression-free survival (adjusted hazard ratio, 0.22; 95% confidence interval, 0.15-0.34; P < .001) and overall survival (adjusted hazard ratio, 0.24; 95% confidence interval, 0.11-0.54; P = .001). Patients who were MRD negative had a higher probability of prolonged progression-free survival than patients with detectable residual disease, regardless of treatment group (RVD vs transplant), cytogenetic risk profile, or International Staging System disease stage at diagnosis. These results were similar after completion of maintenance therapy. Our findings confirm the value of MRD status, as determined by NGS, as a prognostic biomarker in multiple myeloma, and suggest that this approach could be used to adapt treatment strategies in future clinical trials.

Graphical abstract

Figure 1.

Kaplan-Meier survival curves for progression-free survival according to MRD status. (A) According to MRD status at the start of maintenance therapy. The median progression-free survival from the start of maintenance therapy was not reached among MRD⁻ patients, and was 29 months among MRD⁺ patients. (B) After 12 months of maintenance therapy. The median progression-free survival from the completion of maintenance therapy was not reached among MRD⁻ patients, and was 20 months among MRD⁺ patients. (C) Modified by the Simon-Makuch Method. The number of patients at risk in the MRD⁻ group was 0 at the beginning of follow-up because of the time-dependent nature of MRD. Prior to the start of maintenance therapy, all patients were included in the MRD⁺ group; patients who were found to be MRD⁻ on assessment during maintenance were switched to the MRD⁻ group. The median progression-free survival from randomization was not reached among MRD⁻ patients, and was 29 months among MRD⁺ patients.

Figure 2.

Probability of progression-free survival. (A) Adjusted for MRD status and treatment group, (B) cytogenetic risk status, and (C) ISS I and III grouped together, as hazard ratios in these subgroups were numerically identical (C). These curves were constructed according to the results of the Cox model performed on the 366 patients with known MRD status at start of maintenance therapy.

Figure 3.

Kaplan-Meier survival curves for overall survival according to MRD status. (A) Status at the start of maintenance therapy. The overall survival at 4 years after the start of maintenance therapy was 94% among MRD⁻ patients, and 79% among MRD⁺ patients (adjusted hazard ratio for death, 0.24; 95% confidence interval, 0.11-0.54). (B) After 12 months of maintenance therapy. The overall survival at 3 years after the completion of maintenance therapy was 96% among MRD⁻ patients, and 86% among MRD⁺ patients (adjusted hazard ratio for death, 0.26; 95% confidence interval, 0.10-0.68). (C) Modified by the Simon-Makuch method. The number of patients at risk in the MRD⁻ group was 0 at the beginning of follow-up, because of the time-dependent nature of MRD. Prior to the start of maintenance therapy, all patients were included in the MRD⁺ group; patients who were found to be MRD⁻ on assessment during maintenance were switched to the MRD⁻ group. MRD was a strong prognostic factor for overall survival (adjusted hazard ratio, 0.16; 95% confidence interval, 0.08-0.32).