**2. Prevalence**

As mentioned above, MGUS is the most common plasma cell disorders and is a potential precursor of MM. At the Mayo Clinic during 2005, 51% of patients with a monoclonal gamm‐ opathy (n=1,510) had MGUS, 18% MM, 11% amyloidosis, 3% Waldeström macroglobulinemia and 17% other diseases [3].

In 1972, Kyle et al [10] collected serum from 1,200 residents (≥50 y) of Thief River Falls of Minnesota; M-proteins were detected in 15 people, 1.7% men and 0.9% women of the surveyed population (Table 1). In 2006, Kyle et al [1] reported variability in the prevalence of MGUS from a normal population in community practice [11, 12] or in hospitals; data was obtained from studies carried out between 1963 and 2002. It is suggested that this variability might be due to that some studies lacked a geographically defined population in which testing could be performed during a specified period, and that screening methods used in many previous studies are less sensitive than current techniques. To overcome these limitations, Kyle et al [1] used sensitive laboratory procedures to determine the prevalence of MGUS in a large popu‐ lation (n=21,463) in a well-defined geographic area (Table 1): sample of persons aged ≥50 years residing in Olmsted Country (Minnesota, USA). MGUS was found in 3.2% of people in their 5th decade, 5.3% in their 7th decade and 7.5% in over 85 years old (350/9469 men and 344/11,994 women) [1]. Axelsson et al [13] also reported that MGUS is more prevalent in men (1.9%) than in women (1.3%).

The incidence in the population aged 70 years reaches 3% in Caucasian population [4] and 0.7% in Mexican mestizos [14]. The prevalence of MGUS in African Americans was 3-fold higher than in white male veterans, among 4 million African American and white male veterans admitted to Veterans Affairs, between 1980 and 1996 [15] (Table 1). The age-adjusted prevalence of MGUS was 1.97-fold higher in Ghanaian men compared with white men (50-74 y) [16]. Later, they reported the risk of MGUS between white and black male United States veterans could be associated with prior autoimmune, infectious, inflammatory, and allergic disorders; they concluded that various types of immune-mediated conditions might act as triggers for MM/MGUS development [17]. Recently, a disparity in the prevalence, pathogen‐ esis and progression of MGUS between blacks and whites [18] has been reported.


**AGE**: Agarose gel electrophoresis; **CAE**: Cellulose acetate electrophoresis; **CP:** Control prevalence; **HCS-PS:** Hospital cohort study- atomic bomb survivors; **HRGE:** High-resolution gel electrophoresis; **IFE:** Immunofixation; **IE**: Immunoelec‐ trophoresis; **KL:** After scheduled tests for the Korean longitudinal study on health and aging; **LHNC:** Local hospital Nagasaki City**; M/F:** Males/females; **NA:** No available; **PB:** Population based; **PB-HNR:** Population-based Heinz Nixdorf Recall study; **RCS:** Retrospective cohort study; **RS:** Retrospective study; **RS-BS:** Retrospective study of date base of atomic bomb survivors; **RS-IHR:** Retrospective study of inpatient hospitalization records; **SH:** Cross-sectional survey of healthy; **SPEP:** Standard serum electrophoresis; **VA:** Veterans Affairs.

**Table 1.** Studies of epidemiology of MGUS

condition was also referred to as "benign monoclonal gammopathy". However, Kyle recog‐ nized that some patients with MGUS could progress to MM, Waldeström macroglobulinemia, light chain amyloidosis, or related disorders. Thus, Kyle coined the term MGUS in 1978 [8]. In 2003, MGUS is defined by serum M-protein concentration less than 3 g/dL, the bone marrow clonal plasma cell less than 10%, with no evidence of other B-cell proliferation disorders [9].

The objective of this chapter is to describe new concepts and advances concerning the diag‐ nosis, classification, management of patient, risk factors for malignant transformation and new

As mentioned above, MGUS is the most common plasma cell disorders and is a potential precursor of MM. At the Mayo Clinic during 2005, 51% of patients with a monoclonal gamm‐ opathy (n=1,510) had MGUS, 18% MM, 11% amyloidosis, 3% Waldeström macroglobulinemia

In 1972, Kyle et al [10] collected serum from 1,200 residents (≥50 y) of Thief River Falls of Minnesota; M-proteins were detected in 15 people, 1.7% men and 0.9% women of the surveyed population (Table 1). In 2006, Kyle et al [1] reported variability in the prevalence of MGUS from a normal population in community practice [11, 12] or in hospitals; data was obtained from studies carried out between 1963 and 2002. It is suggested that this variability might be due to that some studies lacked a geographically defined population in which testing could be performed during a specified period, and that screening methods used in many previous studies are less sensitive than current techniques. To overcome these limitations, Kyle et al [1] used sensitive laboratory procedures to determine the prevalence of MGUS in a large popu‐ lation (n=21,463) in a well-defined geographic area (Table 1): sample of persons aged ≥50 years residing in Olmsted Country (Minnesota, USA). MGUS was found in 3.2% of people in their 5th decade, 5.3% in their 7th decade and 7.5% in over 85 years old (350/9469 men and 344/11,994 women) [1]. Axelsson et al [13] also reported that MGUS is more prevalent in men (1.9%) than

The incidence in the population aged 70 years reaches 3% in Caucasian population [4] and 0.7% in Mexican mestizos [14]. The prevalence of MGUS in African Americans was 3-fold higher than in white male veterans, among 4 million African American and white male veterans admitted to Veterans Affairs, between 1980 and 1996 [15] (Table 1). The age-adjusted prevalence of MGUS was 1.97-fold higher in Ghanaian men compared with white men (50-74 y) [16]. Later, they reported the risk of MGUS between white and black male United States veterans could be associated with prior autoimmune, infectious, inflammatory, and allergic disorders; they concluded that various types of immune-mediated conditions might act as triggers for MM/MGUS development [17]. Recently, a disparity in the prevalence, pathogen‐

esis and progression of MGUS between blacks and whites [18] has been reported.

preventive strategies of progression of MGUS to malignant conditions.

**2. Prevalence**

in women (1.3%).

and 17% other diseases [3].

112 Multiple Myeloma - A Quick Reflection on the Fast Progress

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].

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).

Monoclonal Gammopathy of Undetermined Significance

http://dx.doi.org/10.5772/56138

115

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

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%,

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

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

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

patients with 0, 1, and 2 risk factors is 2%, 10%, and 46%, respectively.

, CD19-

, CD45-

, CD56+ [40]. They defined two

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

myeloma [36].

respectively [29].

identify aberrant plasma cell populations: CD38+

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 with the progression will be discussed later in this chapter.
