Introduction: Multiple myeloma (MM) is a clonal plasma cell disorder found in the bone marrow that produces a monoclonal immunoglobulin (M-protein). Blood based M-protein diagnostics allows monitoring of disease activity, but with limited sensitivity. Minimal residual disease (MRD) status is a powerful prognostic biomarker. Lack of sensitivity prevents MRD detection by conventional blood based assays. Bone marrow based assays such as next-generation sequencing (NGS) are highly sensitive in measuring MRD. However, bone marrow biopsies introduce a risk of non-representative sampling and are invasive, which limits repeated testing. Frequent MM monitoring during remission could provide actionable information on disease activity and treatment response. Earlier detection of disease progression could lead to early intervention and, potentially, patient survival benefits. The aim of this study was to perform M-protein monitoring on blood samples of MM patients with sensitive targeted mass spectrometry.
Methods: We have developed a targeted mass spectrometry-based MRD blood-test (MS-MRD) that detects clonotypic peptides originating from the variable region of the M-protein. Absolute M-protein quantification (g/L) was performed based on the M-protein peptide and an internal standard, and the data were evaluated for early increases in disease activity. MS-MRD was performed on 926 longitudinally collected sera of 41 MM patients from the IFM 2009 trial (ClinicalTrials.gov number: NCT01191060).
Results: Based on unique patient-specific M-protein peptides, absolute M-protein quantification was feasible in all 41 patients with 1000 times higher sensitivity compared to electrophoretic M-protein quantification. For patients with confirmed progression within the serum sample collection period, MS-MRD revealed the increase of MM disease activity on average 455 days earlier than the progression detected with currently used routine diagnostics (p≤0.0001).
Conclusions: MS-MRD blood-testing is feasible in all patients with multiple myeloma and it has similar sensitivity and prognostic value compared to NGS-MRD evaluation performed on bone marrow. The MS-MRD blood-test paves the way for dynamic MRD monitoring to allow detection of early disease relapse. This minimally invasive MRD test may proof to be well suited to facilitate future clinical implementation of MRD-guided therapy.
