Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: a review of the current understanding of epidemiology, biology, risk stratification, and management of myeloma precursor disease

Abstract

The term monoclonal gammopathy of undetermined significance (MGUS) was coined in 1978. The recent advances in our knowledge about MGUS and smoldering multiple myeloma (SMM) have helped us better understand the pathogenesis of myeloma. It seems that myeloma evolves from a precursor state in almost all cases. We do not completely understand the multistep process from the precursor state to myeloma, but studies like whole genome sequencing continue to improve our understanding of this process. The process of transformation may not be linear acquisition of changes, but rather a branched heterogeneous process. Clinical features that are prognostic of rapid transformation have been identified, but no specific molecular markers have been identified. Even with recent advances, multiple myeloma remains an incurable disease in the vast majority, and intervening at the precursor state provides a unique opportunity to alter the natural history of the disease. A limitation is that a vast majority of patients with precursor disease, especially low-risk MGUS, will never progress to myeloma in their lifetime, and treating these patients is not only unnecessary but may be potentially harmful. The challenge is to identify a subset of patients with the precursor state that would definitely progress to myeloma and in whom interventions will have a meaningful impact. As our understanding of the molecular and genetic processes improves, these studies will guide the selection of high-risk patients more appropriately and ultimately direct a tailored management strategy to either delay progression to symptomatic myeloma or even "cure" a person at this premalignant stage.

Figure 1

Biology of myelomagenesis. Progression from a normal post germinal center B cell to symptomatic myeloma involves a series of genetic and phenotypic changes. Early genetic events can be categorized into two major types – hyperdiploid type and non-hyperdiploid type. These are unified by cyclin D dysregulation (30). The role of 13q appears to be less certain and it may be an early or late event. Secondary genetic changes include Ras mutations, NFκB pathway activating mutations, and inactivating mutations of p53, PTEN or RB pathways (1). Several other genetic changes also occur along the way including secondary translocations, increase in copy number abnormalities, HOXA9 overexpression and Myc upregulation (21, 36). The end result of these changes includes a clonal expansion of abnormal plasma cells that occupy BM stem cell niches (45). Lytic bone lesions are seen due to increased osteoclast activation resulting from RANKL signaling and osteoblast inhibition from DKK1 activity (41, 44). Immune evasion, paracrine and autocrine signaling mediated by cytokine and growth factors are important final steps (46, 51).