Mass spectrometry-based assessment of M protein in peripheral blood during maintenance therapy in multiple myeloma

Abstract

Mass spectrometry (MS) can detect multiple myeloma-derived monoclonal proteins in the peripheral blood (PB) with high sensitivity, potentially serving as a PB assay for measurable residual disease (MRD). This study evaluated the significance of PB MS MRD negativity during posttransplant therapy in patients with newly diagnosed multiple myeloma. Serum samples from 138 patients treated in the phase 3 ATLAS trial of posttransplant maintenance with either carfilzomib, lenalidomide, and dexamethasone, or with lenalidomide alone were analyzed using EXENT MS methodology. We established feasibility of measuring MRD by MS in the PB in the posttransplant setting, despite unavailability of pretreatment calibration samples. There was high agreement between MRD by MS in the PB and paired bone marrow (BM) MRD results at the 10-5 threshold, assessed by either next-generation sequencing (NGS) or multiparameter flow cytometry (MFC) (70% and 67%, respectively). Agreement between PB MS and both BM MRD methods was lowest early after transplant and increased with time. MS negativity was associated with improved progression-free survival (PFS), which, in landmark analysis, reached statistical significance after 18 cycles after transplant. Combined PB/BM MRD negativity by MFC or NGS was associated with superior PFS compared with MRD negativity by only 1 modality. Sustained MS negativity carried similar prognostic performance to sustained BM MRD negativity at the 10-5 threshold. Overall, posttransplant MS assessment was feasible and provided additional prognostic information to BM MRD negativity. Further studies are needed to confirm the role and optimal timing of MS in disease evaluation algorithms. The ATLAS trial is registered at www.clinicaltrials.gov as #NCT02659293.

Graphical abstract

Figure 1.

Agreement between peripheral blood MS and MRD in the BM. Rates of concordant and discordant cases assessed at different time points by NGS at the 10^–5 threshold (A) and by MFC (B).

Figure 2.

Landmark analysis (after cycle 18) of PFS. PFS differences between positive and negative patients by (A) MS, (B) NGS at the 10^–5 threshold, and (C) MFC. Not all patients included in this analysis had the BM MRD testing results available, hence the lower numbers of cases presented in panels B and C.

Figure 3.

Combined impact of peripheral blood MS and BM MRD on PFS. Comparison of PFS in landmark analysis after cycle 18 between those who were double negative (BM and peripheral blood) and those negative in 1 but positive in the other modality. (A) MS and MFC and (B) MS and NGS at the 10^–5 threshold.

Figure 4.

Sustained MS and MRD negativity. PFS of patients with sustained (>12 months) undetectable M protein in the peripheral blood by MS and MRD negative in the BM at the 10^–5 and 10^–6 thresholds.