Proteomic and Metabolomic Analysis of Bone Marrow and Plasma from Patients with Extramedullary Multiple Myeloma Identifies Distinct Protein and Metabolite Signatures

Simple Summary Extramedullary multiple myeloma (EMM) is a rare and aggressive subtype of multiple myeloma which is associated with a poor prognosis. Here, we used mass spectrometry to illustrate that extramedullary multiple myeloma patients have a bone marrow and plasma protein signature that is distinct from multiple myeloma patients without extramedullary spread. We used bioinformatic tools to analyse differentially expressed proteins and verified the increased abundance of three proteins (VCAM1, HGFA, PEDF) in the plasma of patients with EMM. Considering the paucity of informative biomarkers and effective therapeutic approaches for the treatment of EMM, this study may provide direction for the discovery of novel diagnostic and therapeutic approaches and markers of extramedullary progression. Abstract Multiple myeloma (MM) is an incurable haematological malignancy of plasma cells in the bone marrow. In rare cases, an aggressive form of MM called extramedullary multiple myeloma (EMM) develops, where myeloma cells enter the bloodstream and colonise distal organs or soft tissues. This variant is associated with refractoriness to conventional therapies and a short overall survival. The molecular mechanisms associated with EMM are not yet fully understood. Here, we analysed the proteome of bone marrow mononuclear cells and blood plasma from eight patients (one serial sample) with EMM and eight patients without extramedullary spread. The patients with EMM had a significantly reduced overall survival with a median survival of 19 months. Label-free mass spectrometry revealed 225 proteins with a significant differential abundance between bone marrow mononuclear cells (BMNCs) isolated from patients with MM and EMM. This plasma proteomics analysis identified 22 proteins with a significant differential abundance. Three proteins, namely vascular cell adhesion molecule 1 (VCAM1), pigment epithelium derived factor (PEDF), and hepatocyte growth factor activator (HGFA), were verified as the promising markers of EMM, with the combined protein panel showing excellent accuracy in distinguishing EMM patients from MM patients. Metabolomic analysis revealed a distinct metabolite signature in EMM patient plasma compared to MM patient plasma. The results provide much needed insight into the phenotypic profile of EMM and in identifying promising plasma-derived markers of EMM that may inform novel drug development strategies.