MRD Negativity Measured Via Next-Generation Sequencing Predicts Long-Term Survival in Myeloma

Measuring minimal residual disease (MRD) status using next-generation sequencing (NGS) represented a prognostic biomarker for survival in patients with multiple myeloma (MM), according to results from a study published in Blood.

MRD status also appeared to be a more significant predictor of outcome than cytogenetic risk profile or disease stage, the authors, led by Aurore Perrot, MD, PhD, from the Université de Lorraine in France, reported. Results from this trial supported the U.S. Food and Drug Administration’s approval of the clonoSEQ NGS assay for MRD testing in patients with MM or acute lymphocytic leukemia.

Researchers assessed the prognostic value of MRD in patients with transplanteligible, newly diagnosed MM who were enrolled in the phase III Intergroupe Francophone du Myélome (IFM) 2009 trial. Per study protocol, patients were randomized to receive either conventional-dose strategy (8 courses of lenalidomide, bortezomib, dexamethasone [RVD]; n=264) or intensive approach (3 courses of RVD followed by high-dose melphalan and autologous hematopoietic cell transplantation, followed by consolidation with two more cycles of RVD; n=245).

All participants received lenalidomide maintenance therapy for 12 months.

At the start and end of the maintenance therapy period, researchers collected bone marrow samples from all patients; the extracted DNA was then sent for sequencing with commercial NGS kits. Assessment of MRD involved amplifying the extracted DNA by polymerase chain reaction with the use of immunoglobulin gene-specific primers.

MRD negativity was defined as the absence of tumor plasma cells within 1 million bone marrow cells (i.e., a sensitivity of <10-6). Patients who did not enter the maintenance phase or did not achieve at least a very good partial response [VGPR] before entering the maintenance phase were considered MRD positive.

Among the 509 patients included in the intent-to-treat analysis (excluding those who achieved at least a VGPR but who did not have MRD information available), MRDnegativity was achieved at least once during maintenance in 127 patients (25%).

More patients in the transplant arm achieved MRD negativity, compared with the RVD-alone arm (30% [n=73] vs. 20% [n=54]). This translated to an adjusted odds ratio for undetectable MRD of 1.65 (95% CI 1.10-2.49; p=0.02) favoring the intensive approach.

The median duration of followup was 55, 50, and 38 months from randomization, start of maintenance therapy, and completion of maintenance therapy, respectively (ranges not provided). Overall, patients who achieved MRD negativity had significantly longer progression-free survival (PFS) and overall survival, compared with MRD-positive patients. Multivariate analyses adjusting for treatment group and other stratification factors also demonstrated that MRD-negative status was the strongest predictor for PFS (TABLE).

“The MRD negativity rate did not differ according to International Staging System disease stage or cytogenetic risk profile (high vs. standard risk),” the authors added, raising “the possibility that achieving MRD negativity may overcome certain adverse risk factors identified at diagnosis.”

Though these results support the value of MRD status in this setting, the researchers noted that many patients were not evaluable for MRD due to lack of diagnostic sample for calibration, which may be a limitation of this study. “The feasibility of monitoring MRD over time is limited by the invasive bone marrow biopsy procedures, but serum-based tests to facilitate this monitoring are currently undergoing clinical evaluation,” they wrote.

“NGS-determined MRD status enables the identification of patient subpopulations with highly different prognoses,” the researchers concluded. “Consequently, in the future, this endpoint could be used to inform treatment decisions and provide significant reassurance for myeloma patients who achieve MRD negativity, regardless of their cytogenetic risk profile or disease stage. It is also clear that MRD opens the door to evaluation of stratified therapy for MM patients in future randomized clinical trials.”

Corresponding authors report financial relationships with Adaptive Biotechnologies, the manufacturer of the NGS platform used in the trial.

Reference

Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018 September 24. [Epub ahead of print]

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