Multiple myeloma (MM) is an incurable hematopoietic cancer that is characterized by malignant plasma cell infiltration of the bone marrow and/or extramedullary sites. Multi-modality approaches including "novel agents," traditional chemotherapy, and/or stem cell transplantation are used in MM therapy. Drug resistance, however, ultimately develops and the disease remains incurable for the vast majority of patients. In this chapter, we review both tumor cell-autonomous and non-autonomous (microenvironment-dependent) mechanisms of drug resistance. MM provides an attractive paradigm highlighting a number of current concepts and challenges in oncology. Firstly, identification of MM cancer stem cells and their unique drug resistance attributes may provide rational avenues towards MM eradication and cure. Secondly, the oligoclonal evolution of MM and alternation of "clonal tides" upon therapy challenge our current understanding of treatment responses. Thirdly, the success of MM "novel agents" provides exemplary evidence for the impact of therapies that target the immune and non-immune microenvironment. Fourthly, the rapid pace of drug approvals for MM creates an impetus for development of precision medicine strategies and biomarkers that promote efficacy and mitigate toxicity and cost. While routine cure of the disease remains the ultimate and yet unattainable prize, MM advances in the last 10-15 years have provided an astounding paradigm for the treatment of blood cancers in the modern era and have radically transformed patient outcomes.
Keywords: Drug resistance; Immunotherapy; Microenvironment; Multiple myeloma; Signaling pathways.