Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy, which is predominantly a disease of older adults (the median age at diagnosis is 70 years). The slow progression from asymptomatic stages and the late-onset of MM suggest fundamental differences compared to many other hematopoietic system-related malignancies. The concept discussed in this review is that age-related changes at the level of terminally differentiated plasma cells act as the main risk factors for the development of MM. Epigenetic and genetic changes that characterize both MM development and normal aging are highlighted. The relationships between cellular aging processes, genetic mosaicism in plasma cells, and risk for MM and the stochastic processes contributing to clonal selection and expansion of mutated plasma cells are investigated. In line with the DNA damage accumulation theory of aging, in this review, the evolution of monoclonal gammopathy to symptomatic MM is considered. Therapeutic consequences of age-dependent comorbidities that lead to frailty and have fundamental influence on treatment outcome are described. The importance of considering geriatric states when planning the life-long treatment course of an elderly MM patient in order to achieve maximal therapeutic benefit is emphasized.

Keywords: Frailty; Gammopathy; Multiple myeloma; Vulnerable patient; aging.

Fig. 1

Schematic illustration of the role of fundamental cellular and molecular mechanisms of aging in the pathogenesis of multiple myeloma. The scheme highlights stages of B cell differentiation and myelomagenesis, showing how myeloma progresses from a normal plasma cell to monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to full blown multiple myeloma. Aging promotes the genesis of DNA damage and mutations, facilitates the selection of premalignant and malignant clones, impairs the mechanisms involved immunosurveillance and elimination of malignantly transformed cells, and exacerbates cellular and molecular mechanisms contributing to tumor cell survival, proliferation, extramedullary tumor formation, and tumor angiogenesis. Abbreviations used: SASP, senescence-associated secretory phenotype; MGUS, monoclonal gammopathies of undetermined significance; SMM, smoldering multiple myeloma