Advances in understanding monoclonal gammopathy of undetermined significance as a precursor of multiple myeloma

Abstract

Monoclonal gammopathy of undetermined significance (MGUS) affects at least 3% of the population above the age of 50 and is the precursor to multiple myeloma (MM), an incurable malignancy of plasma cells. Recent advances in MGUS include: an improved understanding of the pathogenesis of MGUS and its progression to MM, involving molecular events intrinsic to the malignant plasma cell as well as the microenvironment; novel techniques to assess risk for progression to MM using serum-free light-chain analysis and immunophenotyping; and a renewed interest in chemoprevention of MM. In the future, continued improvement in our understanding of MGUS will lead to the development of better biomarkers for prognosis and therapies for chemoprevention of MM.

Trial registration: ClinicalTrials.gov NCT00480363.

Keywords: MGUS; monoclonal gammopathy of undetermined significance; multiple myeloma; pathogenesis.

Figure 1. Multistep model for the molecular pathogenesis of MGUS and myeloma

Four early, partially overlapping oncogeneic events (cyclin D dysregulation, hyperdiploidy, chromosome 13 deletion, and primary IgH translocations) are shared by MGUS and MM tumors. The relative timing of these four events is not fully understood, although primary IgH translocations are thought to occur in germinal center B cells. Other oncogenic events are thought to occur later, and mostly in MM tumors, but sometimes are found in MGUS tumors. Late oncogenic events (e.g., MYC rearrangement and p53 activation) appear to occur mainly in advanced MM tumors. Estimates of the timing of various events are indicated by solid and dashed (reflecting less certainty) lines. See text for additional details. MGUS: Monoclonal gammopathy of undetermined significance; MM: Multiple myeloma.

Figure 2. Proposed models for the patterns of the MGUS to MM progression

MGUS: Monoclonal gammopathy of undetermined significance; MM: Multiple myeloma; SMM: Smoldering multiple myeloma. Redrawn with permission from [51], Nature Publishing Group.

Figure 3. Abnormal serum-free light-chain ratio may signal the onset of multiple myeloma

Modified with permission from [50].