Extramedullary multiple myeloma (EMD) is a highly aggressive manifestation of multiple myeloma (MM) characterized by the spread of malignant plasma cells outside the bone marrow microenvironment to distal organs and tissues. EMD is associated with poor prognosis and significantly reduced overall survival (OS) compared to MM confined to the bone marrow. Yet, the molecular mechanisms underlying EMD remain poorly understood.

To address this, we analysed bone marrow mononuclear cells (BMNCs) from a small cohort of MM patients with (n=9) and without EMD (n=8). BMNCs samples (medullary MM: n=8, EMD: n=9) were analysed with Orbitrap Fusion Tribrid and Q-Exactive MS systems. For total RNA analysis, libraries were prepared and sequenced using the TruSeq Rapid PE Cluster Kit, TruSeq Rapid SBS (Illumina) and run on a NextSeq500.

We identified a clear change in the proteomic profile of EMD and MM BMNCs. 4,751 proteins were identified, with 318 showing significant differential abundance (ANOVA P < 0.05, fold change >1.5) between the two cohorts. Of these, 154 proteins were increased and 148 were decreased in abundance in EMD. Cell adhesion, invasion, and migration proteins including those involved in leukocyte transendothelial migration were significantly increased in abundance in the EMD cohort highlighting their role in tumour dissemination. Conversely, proteins decreased in EMD BMNCs were associated with metabolic pathways such as TCA cycle. Transcriptomic analysis showed increased ATP-binding cassette sub-family C member 4 (ABCC4) expression, linked to selinexor resistance. In addition, upregulated S100 Calcium Binding Protein A6 (S100A6) correlated with poorer overall survival and bortezomib resistance, while Transmembrane Protein 183A (TMEM183A) upregulation correlated with tumour progression.

This study highlights distinct transcriptomic and proteomic profiles in MM patients with aggressive EMD, aiming to inform personalised therapies in future larger cohort studies.