Differential diagnosis of Monoclonal Gammopathy of Undetermined Significance

Monoclonal gammopathies of undetermined significance (MGUS) are high-prevalence (4.2% in adults > 50 years) asymptomatic conditions that can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma (MM) and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal (M) protein, as seen in AL amyloidosis and related conditions. Differential diagnosis of asymptomatic and symptomatic monoclonal gammopathies is the determinant for starting therapy. The criteria for determining end-organ damage should include markers of organ injury caused by the M-protein. Patient assessment and optimal follow-up are now performed using risk stratification models that should take into account also the risk of developing AL amyloidosis. Individuals with low-risk MGUS (∼40% of all MGUS) need limited assessment and very infrequent follow-up. The ongoing development of novel molecular biomarkers and advanced imaging techniques will improve the identification of high-risk patients who may benefit from early therapeutic intervention through innovative clinical trials.