Differential diagnosis of monoclonal gammopathy of undetermined significance Giampaolo Merlini 1,2 and Giovanni Palladini 1,2 1 Amyloidosis Research and Treatment Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy; and 2 Department of Molecular Medicine, University of Pavia, Pavia, Italy Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic plasma cell disorder occurring in 4.2% of adults  50 years of age, which can progress into symptomatic diseases either through proliferation of the plasma cell clone, giving rise to multiple myeloma and other lymphoplasmacellular neoplasms, or through organ damage caused by the monoclonal protein, as seen in light-chain 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 monoclonal protein. Patient assessment and optimal follow-up are now performed using risk stratification models that should also take into account the risk of developing AL amyloidosis. Patients with low-risk MGUS (approximately 40% of all MGUS patients) 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. Introduction Robert Kyle coined the term monoclonal gammopathy of undeter- mined significance (MGUS) in 1978 after the observation that asymptomatic patients with a monoclonal protein (M-protein) had higher risk of developing multiple myeloma (MM), Waldenstro ¨m macroglobulinemia (WM), light-chain amyloidosis (AL), or related conditions. MGUS is a premalignant clonal disorder that is present in more than 4% of the general white population older than 50 years of age 1,2 and is associated with a 1%/y risk of progression to MM or related malignancies. Because the transition from MGUS into a malignant, symptomatic condition is an evolving process, 3 the differential diagnosis between MGUS and these diseases is fre- quently challenging. MGUS may progress toward symptomatic conditions, requiring the initiation of treatment, through 2 general mechanisms (Figure 1): (1) progression of the proliferative charac- teristics toward smoldering MM (SMM), MM, and other lympho- plasmacellular disorders, which account for approximately 90% of the progression; or (2) the development of end-organ damage caused by the M-protein such as AL amyloidosis, light chain deposition disease (LCDD), and other rarer conditions, which account for approximately 10% of the progression. Because most MGUS progression occurs toward MM, little attention has been dedicated to the development of other disorders caused by the M-protein. Recognition of an M-protein Most M-proteins are detected incidentally during the investigation of other conditions. There is consensus that population-based screening should not be performed considering the generally low risk of progression to a malignant disorder and the related emotional burden. However, in the presence of clinical suspicion of MM, WM, AL amyloidosis, or related disorders, the clinician should always screen for an M-protein. Although virtually 100% of patients with MM and WM can be identified by serum electrophoresis and quantitative serum free light chain (FLC) assays, serum and urine immunofixation are also required to achieve the best diagnostic sensitivity for other serious conditions such as AL amyloidosis or LCDD. 4,5 Prevalence and risk factors Using the serum FLC assay and immunofixation electrophoresis, Mayo Clinic investigators determined the overall age- and sex- adjusted prevalence of conventional MGUS in persons 50 years of age or older in Olmsted County to be 3.4%. 1,6 Considering that the prevalence of light-chain MGUS is 0.8%, the overall MGUS prevalence is 4.2% (95% confidence interval, 3.9-4.5). 6 Studies in both white and Japanese populations demonstrate a clear increase in prevalence with age. The prevalence is also affected by sex: 3.7% and 2.9% in white men and women, respectively, and 2.8% and 1.6% in Japanese men and women, respectively. MGUS is twice as prevalent in black adults (5.9%-8.4%). 7 The etiology of MGUS is unknown, and previous studies support a role of both genetic and environmental factors. A family history of MGUS or MM increases the risk of MGUS by approximately 3.3- and 2-fold, respectively, suggesting a shared environmental and/or genetic effect. 8-10 Radiation exposure, particularly at a younger age, increases the risk of MGUS significantly, but not that of malignant progression. 11 The use of certain pesticides, 12 as well as African ethnicity, obesity, and increasing age are associated with an excess risk of MGUS. 13 Distinct clinical subtypes of MGUS and related disorders Large epidemiological and clinical studies have led Mayo Clinic investigators to define 3 distinct clinical subtypes of MGUS, each with a different mode of progression: non-IgM MGUS, by far the most common; IgM-MGUS; and light-chain MGUS (Table 1). 14 Non-IgM MGUS and light-chain MGUS have a plasma cell (PC) phenotype and can progress to MM or related PC disorders, whereas the 15%-20% of patients with IgM-MGUS usually have a lymphoid THE SPECTRUM OF PLASMA CELL DYSCRASIAS Hematology 2012 595