**4. Risk factors for malignant transformation of MGUS**

In 2010, Wadhera and Rajkumar [19] on the basis of a systematic review of prevalence of MGUS selected 14 of 460 articles, which met the inclusion criteria for their review [10, 12, 15, 16, 20-22] (Table 1). They discussed study types, method sensibility and availability to detect M-protein and diagnostic criteria. They conclude that the prevalence increases with age and is affected by race, sex, among other factors. Further studies of prevalence are shown in Table 1 [23-26]. One long-term research studied a population-based of 1,384 patients with MGUS from the 11 counties of southeastern Minnesota who were evaluated from 1960 to 1994 [2]. These patients were observed for a total of 11,009 person-years. Of the identified MGUS, 115 progressed to MM or related disorders. At 10 years, 10% had progressed; 20 years, 21% had progressed; and at 25 years, 26% had progressed. The conclusion of these authors is that the risk of progression is about 1% per year. In 2003, a study reported that relative risk of progression was 16-fold higher in the patients with IgM MGUS than in the white population of the Iowa Surveillance [27]. Furthermore, risk for progression to lymphoma or a related disorder at 10 years after the diagnosis of MGUS was 14% with an initial M-protein concentration of 0.5 g/dL or less, 26% with 1.5 g/dL, 34% for 2.0 g/dL, and 41% for more than 2.5 g/dL [27]. Risk factors associated

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

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

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

with the progression will be discussed later in this chapter.

114 Multiple Myeloma - A Quick Reflection on the Fast Progress

or more immunoglobulin class levels).

methodology [35].

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

Risk factors fortransformation of MGUS to malignant condition have been analyzed in several studies. An abnormal serum free light chain ratio (κ/λ), non-IgG MGUS, and a high serum M protein level (≥1.5 g/dL) are three major risk factors for the progression of MGUS to myeloma [36].

Based on the clinical markers still available, two independent studies were able to establish predictive risk models from MGUS to MM for each clinical type of MGUS. The first model, proposed by a group at the Mayo Clinic identifies three main risk factors for progression: serum M-protein >1.5 g/dL, IgG subtype and normal free light chain ratio. The probability of progression of MGUS to malignant monoclonal gammopathy is 1% per year, with an estimated risk of progression of 34% over 20 years [37]. At 20 years of follow-up, absolute risk of progression for MGUS patients with 0, 1, 2, and 3 risk factors are 5%, 21%, 37%, and 58%, respectively [29].

Immunophenotyping is an attractive technique to potentially identify high levels of malignant plasma cells among normal plasma cells [38] and for the differential diagnosis between MGUS and MM [39]. The second model, proposed by a Spanish group, introduces a novel prognostic criterion for MGUS. This group has established a multiparameter flow cytometry as a tool to identify aberrant plasma cell populations: CD38+ , CD19- , CD45- , CD56+ [40]. They defined two factors: (1) a plasma cell/normal bone marrow plasma cell ratio >95% associated with higher risk of progression, and (2) DNA aneuploidy. Free progression survival at 5 years for MGUS patients with 0, 1, and 2 risk factors is 2%, 10%, and 46%, respectively.

Both models present advantages and disadvantages with regard to the risk stratification of patients with MGUS [41]. The Mayo Clinical model may be useful in routine clinical practice, but the disadvantages of the model are its poor discrimination of the risk of progression between groups. On the other hand, the Salamanca model is a superior model, in particular, to identify a truly high-risk MGUS population; however, its main disadvantages are invasive‐ ness (it requires a bone marrow aspirate), technical complexity and high cost.

The biological events related to progression from normal plasma cells to MM precursor disease and to MM involve many overlapping oncogenic steps that differently affect each individual [42]. Several authors discuss the very early and partially overlapping molecular pathogenic events that are shared by MGUS, and how they are associated to progression at the MGUS to MM transition [43-45].
