Multiple myeloma is a haematological cancer characterised by proliferation of clonal plasma cells (PC) in the bone marrow (BM) that is preceded by a precursor stage, monoclonal gammopathy of undetermined significance (MGUS). The BM plays a role in supporting myeloma PC and in MGUS to myeloma progression. It is difficult to clinically differentiate MGUS patients who will rapidly progress to myeloma (3-5 years) compared with those likely to remain stable. We aimed to discover blood-based factors that could differentiate myeloma and MGUS and to determine the source of these proteins.
Olink Explore HT that allows relative quantitation of up to 5000 proteins was performed on peripheral blood plasma from MGUS and myeloma patients (n=9/group). Single-cell RNA sequencing (scRNAseq; 10xGenomics Chromium [V3.1]) was performed on bone marrow cells isolated from 5 myeloma trephine biopsies (n=2 newly diagnosed, n=3 treated), and 1 non-cancer control.
Proteomic analysis identified 516 proteins that were significantly correlated with BM PC% in MGUS and myeloma patients (Spearman p < 0.05), including 89 significantly upregulated proteins (FDR p < 0.05; LIMMA) and 10 significantly downregulated in myeloma compared with MGUS patients. To identify the source of these proteins scRNA was performed on 45,863 BM cells. The analyses revealed that factors dysregulated in the blood of myeloma patients include 75 PC derived factors (eg. BCMA, SLAMF7) and 24 proteins that are never or rarely expressed by myeloma PCs, including those expressed by BM osteoblasts (eg. SFRP4, VIT) and adipocytes (eg. CCL14).
We have discovered both plasma cell derived factors and microenvironment derived factors significantly upregulated in peripheral blood plasma from myeloma compared with MGUS samples. Future studies will investigate these factors in progressing MGUS compared to those with stable MGUS (>5years). The ability to discover blood-based factors associated with progression will provide opportunities to identify individuals with high-risk MGUS.