MGUS to myeloma: a mysterious gammopathy of underexplored significance

All cases of multiple myeloma (MM) are preceded by precursor states termed monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM). Genetic analyses of MGUS cells have provided evidence that it is a genetically advanced lesion, wherein tumor cells carry many of the genetic changes found in MM cells. Intraclonal heterogeneity is also established early during the MGUS phase. Although the genetic features of MGUS or SMM cells at baseline may predict disease risk, transition to MM involves altered growth of preexisting clones. Recent advances in mouse modeling of MGUS suggest that the clinical dormancy of the clone may be regulated in part by growth controls extrinsic to the tumor cells. Interactions of MGUS cells with immune cells, bone cells, and others in the bone marrow niche may be key regulators of malignant transformation. These interactions involve a bidirectional crosstalk leading to both growth-supporting and inhibitory signals. Because MGUS is already a genetically complex lesion, application of new tools for earlier detection should allow delineation of earlier stages, which we term as pre-MGUS. Analyses of populations at increased risk of MGUS also suggest the possible existence of a polyclonal phase preceding the development of MGUS. Monoclonal gammopathy in several patients may have potential clinical significance in spite of low risk of malignancy. Understanding the entire spectrum of these disorders may have broader implications beyond prevention of clinical malignancy.