MGUS to myeloma: a mysterious gammopathy of underexplored significance

Abstract

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.

Figure 1.

Tumor and microenvironment in natural history of gammopathies. Emerging data suggest that much of the genomic complexity and intraclonal heterogeneity is already well established by MGUS stage. The mechanism underlying the origins of this instability is not clear but may involve a big bang followed by clonal evolution. Clinical dormancy of MGUS or AMM lesions depends in part on interactions with the tumor microenvironment, and alteration of these signals can promote changes in growth kinetics at the population level, manifested as malignant transformation. Genetic complexity of MGUS also points to the presence of proximate, potentially less complex lesions termed pre-MGUS. We hypothesize that these lesions emerge from an initial polyclonal response to endogenous or exogenous antigens. Tumor evolution is driven by both tumor-intrinsic and tumor-extrinsic events that may be interdependent.