Disease-state and progression biomarker discovery in multiple myeloma plasma

Multiple Myeloma (MM) develops from well-defined precursors—Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM)—where patients remain stable or may rapidly progress. Bone marrow (BM) biopsies are used for staging and identifying high-risk genomic abnormalities associated with progression. However, BM biopsies are invasive and cannot be repeated often for monitoring tumor burden in the precursor setting, and these patients are limited to monitoring a few markers within peripheral blood (PB) for signs of progressive disease. Deep proteome profiling of PB plasma may advance non-invasive precursor disease staging, monitoring, and characterization. Precursor patients are currently monitored via a few peripheral blood biomarkers for signs of progressive disease. Plasma proteome profiling to identify effective biomarkers has been hindered by the wide dynamic range of plasma and often low abundance of disease-specific markers.

Here we performed the first comprehensive analysis of the plasma proteome of MM and its precursor conditions using the Olink proximity extension assay (PEA) that targets ca. 3000 proteins. We profiled 529 PB plasma samples from 485 individuals, including MGUS (n=100), SMM (n=203), MM (n=100), and age-matched healthy donors (HDs) (n=82). Samples from patients with progressive disease (n=32) and stable precursor disease (n=32) with matched clinical follow-up time were also profiled. Analysis of the data enabled us to develop a classifier that utilizes plasma proteins alone to accurately classify disease stages and identified a prognostic protein signature associated with progressive disease. Advancements are underway to validate our high-risk disease candidates, test the performance of an improved risk stratification model in external cohorts, and determine how best to implement proteome profiling into clinical practice.