Abstract
In order to meet the challenges in data evaluation and comparability between studies in multiple myeloma (MM) minimal residual disease (MRD) assessment, the goal of the current study was to provide a step-by-step evaluation of next-generation sequencing (NGS) and multicolor flow cytometry (MFC) data. Bone marrow (BM) sample pairs from 125 MM patients were analyzed by NGS and MFC MM MRD methods. Tumor load (TL) and limit of detection (LOD) and quantification (LOQ) were calculated. The best-fit MRD cut-off was chosen as 1 × 10−5, resulting in an overall 9.6% (n overall = 12 (NGS n = 2, MFC n = 10)) nonassessable cases. The overall concordance rate between NGS and MFC was 68.0% (n = 85); discordant results were found in 22.4% (11.2% (n = 14) of cases in each direction. Overall, 55.1% (n = 60/109) and 49.5% (n = 54/109) of patients with a serological response ≥ very good partial response (VGPR) showed BM MRD negativity by NGS and MFC, respectively. A good correlation in the TL assessed by both techniques was found (correlation coefficient = 0.8, n = 40, p < 0.001). Overall, our study shows good concordance between MM BM MRD status and TL when comparing NGS and MFC at a threshold of 10–5. However, a sufficient number of analyzed events and calculation of MRD key metrics are essential for the comparison of methods and evaluability of data at a specific MRD cut-off.
Highlights
Minimal residual disease (MRD) is defined as a small number of malignant cells that persist during or after treatment and cannot be detected by serological or cytological methods
In next-generation sequencing (NGS), the median number of cell equivalents analyzed was 1.1 × 106 (1.8 × 105 –2.3 × 106 ). This resulted in a median NGS limit of detection (LOD) level of 1.7 × 10−6 (8.1 × 10−7 –1.9 × 10−4 ) and a median NGS
MRD-positive results were cases, and concordant MRD-negative results were found in 34.4% (n = 43), resulting in an overall
Summary
Minimal residual disease (MRD) is defined as a small number of malignant cells that persist during or after treatment and cannot be detected by serological or cytological methods. State-of-the-art methods for the highly sensitive and standardized detection of bone marrow (BM) MRD in multiple myeloma (MM) include next-generation sequencing (NGS) and multicolor flow cytometry (MFC). In MFC, achieved through a two-tube, eight-color antibody panel, the identification of malignant cells is based on an aberrant immunophenotype displayed by neoplastic MM cells compared to normal plasma cells [2]. Based on optimal requirements, including sample quality and sample processing, both MM MRD detection methods have been described to reach a sensitivity of up to one tumor cell per 1,000,000 BM cells (10−6 ) [1,3]. In MM, the presence of residual tumor cells in BM is considered the major cause of relapse
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