**3. Diagnosis and classification of patient with MGUS**

The UK Myeloma Forum and the Nordic Myeloma Study Group have proposed guidelines for the effective clinical investigation of patients with M-proteins and management of patients with MGUS [28]. These guidelines are almost entirely based on expert consensus opinion. They were searched by MEDLINE and EMBASE systematically for publications from 1950 to October 2008. They suggest that screening normal populations for M-protein for clinical purposes are not recommended. It was suggested that serum protein electrophoresis should be performed if there is clinical suspicion of an M-protein or when the abnormal test results (erythrocyte sedimentation rate >30 mm/h or plasma viscosity; unexplained anemia, hyper‐ calcemia or renal failure; raised total protein/globulin or immunoglobulins; reduction of one or more immunoglobulin class levels).

The UK Myeloma Forum and the Nordic Myeloma Study Group guidelines specifically state that there is no evidence supporting the use of serum free light chain in monitoring patients [28]. By contrast, the International Myeloma Working Group members suggest that serum free light chain analysis may be a useful adjunctive test in monitoring patients with MGUS [29-33]. The ratio of κ/λ is critical to the interpretation, because an abnormal serum free light chain ratio should only be present in the context of a plasma cell dyscrasia with severe renal failure or other B-cell lymphoproliferative disorders [34]. It is important to note that serum free light chain analysis by immunoassay is much more sensitive than the serum protein electrophoresis methodology [35].

In 2010, International Myeloma Working Group has recommended a new classification of MGUS [36]; each type must meet all the criteria set out: Non-IgM (IgG or IgA) MGUS with serum M-protein <3 g/dL, clonal bone marrow plasma cells <10%, absence of end-organ damage, such as CRAB (hypercalcemia, renal insufficiency, anemia and bone lesions); IgM MGUS with serum M-protein <3 g/dL, clonal bone marrow lymphoplasmacytic cells <10%, absence of end-organ damage; and light chain-MGUS with abnormal free light chain ratio <0.26 or >1.65, increased level of the appropriate involved light chain, increased κ free light chain in patients with ratio >1.65 and increased λ free light chain in patients with ratio <0.26, no immunoglobulin heavy chain expression on immunofixation, clonal bone marrow plasma cells <10%, and absence of end-organ damage, such as CRAB [19, 36]. Each clinical type is charac‐ terized by unique intermediate stages and progression events. The intermediate stages with high risk of progression are [36]: (i) smoldering MM (SMM: IgG or IgA M-protein ≥3 g/dL, and/or clonal bone marrow plasma cells ≥10%, and absence of end-organ damage, CRAB); (ii) smoldering Waldenström macroglobulinemia (IgM M-protein ≥3 g/dL and/or clonal bone marrow lymphoplasmacytic infiltration ≥10%, no evidence of anemia constitutional symp‐ toms); and (iii) idiopathic Bence Jones proteinuria (urinary M-protein on urine protein electrophoresis ≥500 mg/24 h and/or clonal bone marrow plasma cells ≥10%, no immunoglo‐ bulin heavy chain expression on immunofixation, absence of end-organ damage, CRAB).
