Shaping the Treatment Paradigm Based on the Current Understanding of the Pathobiology of Multiple Myeloma: An Overview

SIMPLE SUMMARY: Advances in our understanding of the causes of multiple myeloma and the mechanisms of disease progression have facilitated significant changes in the way we treat this incurable blood cancer. This review summarizes the genetic changes critical in disease development, the dysregulation of the immune system and how cells of the tumour microenvironment interact with and promote the survival of malignant plasma cells. We then provide a comprehensive overview of recent practice changing clinical trials incorporating novel agents into upfront treatment regimens as well as explore innovative immunotherapies, designed to overcome the dysfunctional immune system, and small molecules with novel mechanisms of action that are currently actively investigated in the relapsed and/or refractory disease setting. ABSTRACT: Multiple myeloma is an incurable malignancy which despite progressive improvements in overall survival over the last decade remains characterised by recurrent relapse with progressively shorter duration of response and treatment-free intervals with each subsequent treatment. Efforts to unravel the complex and heterogeneous genomic alterations, the marked dysregulation of the immune system and the multifarious interplay between malignant plasma cells and those of the tumour microenvironment have not only led to improved understanding of myelomagenesis and disease progression but have facilitated the rapid development of novel therapeutics including immunotherapies and small molecules bringing us a step closer to therapies that no doubt will extend survival. Novel therapeutic combinations both in the upfront and relapsed setting as well as novel methods to assess response and guide management are rapidly transforming the management of myeloma.