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

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.

Keywords: genomic aberrations; minimal residual disease; multiple myeloma; tumour microenvironment.

Figure 1

Myeloma pathogenesis is characterised by (A) genomic aberrations, dysregulation of (B) the immune tumour microenvironment (TME) and (C) the multifarious interplay between myeloma cells and the non-immune TME. (A) Familial clustering, racial predisposition and genome wide association studies highlight a familial predisposition for myeloma. Primary genetic events may occur before development of myeloma while secondary events and various somatic mutations lead to clonal evolution and heterogeneity and ultimately disease progression and resistance to therapy. (B) The dysregulated immune system is characterised by progressive increase in cytotoxic T and NK cells which through reduced expression of co-stimulatory receptors and increased expression of inhibitory receptors become dysfunctional. Helper T-cells in turn are diminished with a shift to more pro-inflammatory and immunosuppressive cytokine milieu exerted by T_H2 and regulatory T cells. (C) The interaction between malignant plasma cells and various TME components, especially bone marrow suppressor cells, is critical in promoting myeloma cell survival and resistance to therapy. Created with BioRender.com.