Multiple myeloma (MM) is characterized by the clonal expansion of plasma cells in the bone marrow that results in end-organ damage, including hypercalcemia, renal dysfunction, infection, anemia, and bone disease. Despite the introduction of novel therapeutics, MM remains an incurable disease mainly due to repeated relapses and resistance to current chemotherapies. The development of extramedullary multiple myeloma (EMM), an aggressive form of MM associated with the colonisation of soft tissues or organs by myeloma cells, is associated with a poor prognosis. There remains a critical unmet need for effective treatments for patients with refractory disease and aggressive extramedullary disease. Given the potential of predictive biomarker panels to optimise treatment regimens, a phosphoproteomic analysis based on ex vivo drug responses to a selection of drug classes was performed. Results showed an increased abundance of proteins and phosphoproteins associated with cell adhesion and a decreased abundance of proteins and phosphoproteins associated with protein translation in multi-drug resistant myeloma cells based on ex vivo drug response. Furthermore, a proteomic analysis of MM patient plasma stratified based on ex vivo drug responses identified circulating proteins, including interleukin-15, as potential predictive biomarkers of drug response. Using label-free mass spectrometry, distinct alterations in the proteomic profile of bone marrow mononuclear cells from EMM patients compared to MM patients were identified. Bioinformatic analysis revealed an increased abundance of proteins linked to a poor prognosis in MM, and potential cellular mechanisms, including leukocyte transendothelial migration, associated with EMM. Proteomic and metabolomic evaluation of plasma samples from MM patients with and without extramedullary spread confirmed a distinct phenotypic change in EMM patients. Three proteins, namely, vascular cell adhesion molecule 1, hepatocyte growth factor activator, and pigment epithelium derived factor, were verified as promising biomarkers of EMM. Overall, this thesis provides novel insights into aggressive phenotypes of MM and identifies promising biomarkers for future validation studies.