INTRODUCTION — Monoclonal gammopathy of undetermined significance (MGUS) is a clinically asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. It is defined by the presence of a serum monoclonal protein (M protein) at a concentration <3 g/dL, a bone marrow with <10 percent monoclonal plasma cells, and absence of end-organ damage (lytic bone lesions, anemia, hypercalcemia, kidney impairment, hyperviscosity) related to the proliferative process.
MGUS occurs in over 3 percent of the White population over the age of 50 and is typically detected as an incidental finding when individuals undergo a protein electrophoresis as part of an evaluation for a wide variety of clinical symptoms and disorders (eg, peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia, or elevated erythrocyte sedimentation rate).
There are three distinct clinical types of MGUS, each with a risk of progressing through a unique intermediate (more advanced) premalignant stage and then to a malignant plasma cell dyscrasia or lymphoproliferative disorder [1]:
●Non-IgM MGUS (IgG, IgA, or IgD MGUS) – Non-IgM MGUS is the most common subtype of MGUS and has the potential to progress to smoldering (asymptomatic) multiple myeloma and to symptomatic multiple myeloma. Less frequently, these individuals progress to AL amyloidosis, light chain deposition disease, or another lymphoproliferative disorder.
●IgM MGUS – IgM MGUS accounts for approximately 15 percent of MGUS cases. It is considered separately from the non-IgM MGUS because it has the potential to progress to smoldering Waldenström macroglobulinemia and to symptomatic Waldenström macroglobulinemia, and less often to lymphoma or AL amyloidosis. Infrequently, IgM MGUS can progress to IgM multiple myeloma.
●Light chain MGUS (LC-MGUS) – LC-MGUS is a unique subtype of MGUS in which the secreted M protein lacks the immunoglobulin heavy chain component. LC-MGUS may progress to light chain smoldering multiple myeloma (idiopathic Bence Jones proteinuria) and to light chain multiple myeloma, AL amyloidosis, or light chain deposition disease [2].
The diagnosis of individuals with MGUS will be discussed here [3-6]. The management of individuals with MGUS, the recognition of serum or urinary M proteins, and a discussion of the clinical features, laboratory manifestations, and diagnosis of multiple myeloma and other plasma cell dyscrasias are presented separately.
●(See "Clinical course and management of monoclonal gammopathy of undetermined significance".)
●(See "Laboratory methods for analyzing monoclonal proteins".)
●(See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
●(See "Monoclonal immunoglobulin deposition disease".)
EPIDEMIOLOGY — MGUS was found in approximately 1 to 2 percent of adults in studies from Sweden, the United States, France, and Japan [7-11]. The mean age at diagnosis is 70 years, and less than 2 percent of individuals are diagnosed before the age of 40 [12,13]. The incidence and prevalence rises with individual age [12,14,15], is higher in men than women [12], and is two- to threefold higher in Africans and African Americans compared with White Americans [16-19].
The incidence of MGUS in men is estimated to be 120 per 100,000 at age 50 and increases to 530 per 100,000 by the age of 90. The corresponding rates for women are 60 per 100,000 population at age 50, and 370 per 100,000 at age 90 [15].
The best estimates of prevalence come from population-based studies of a geographically defined area during a specific time period. Factors that influence the findings of such studies include demographic features of the screened population (ie, age, sex, race), the presence of risk factors for MGUS in the population (eg, occupational and environmental risk factors, immune status, and familial risk), and logistical features of the study (eg, how the study identified populations to screen, the sensitivity of the diagnostic tests used, and the diagnostic criteria used) [20]. Higher sensitivity techniques, such as mass spectrometry, are able to detect MGUS in an even greater percentage of the population [21,22].
The prevalence of MGUS among a well-defined, largely White population was determined by agarose gel electrophoresis followed by immunofixation in 21,463 of the 28,038 enumerated residents (77 percent) of Olmsted County, Minnesota, who were ≥50 years of age [12]:
●The prevalence of MGUS in individuals ≥50, ≥70, and ≥85 years of age was 3.2, 5.3, and 7.5 percent, respectively.
●Age-adjusted rates for individuals ≥50 were significantly higher in men than in women (4.0 versus 2.7 percent).
●Further evaluation noted the prevalence of light chain-MGUS and MGUS in individuals over age 50 was 0.8 and 3.4 percent, respectively [23].
Many studies have demonstrated the effects of race on MGUS frequency. A study from Ghana used stratified random sampling to estimate the incidence of MGUS in Black men from western Africa at twice that of the White population from Minnesota [19]. A two- to threefold higher frequency in MGUS among Black Americans was also seen in a large study of inpatients from United States Veterans Affairs hospitals [18] and a large population-based study of American women [24]. The latter study also showed that the increased risk of MGUS seen in Black Americans persists in a cohort of women of similar socioeconomic status. These and other studies suggest that the racial predisposition to MGUS and multiple myeloma observed in Black individuals is likely related to shared genetics, rather than environmental factors [19,24].
There is a paucity of information regarding the incidence in other populations. A study from Japan that used an older method for screening suggests that Japanese adults may have a slightly lower incidence than that seen in White Americans from Minnesota [11]. The limited data available also suggest that the prevalence of MGUS in Mexicans is less than in White Minnesotans [25].
Genetic predisposition — While most cases of MGUS appear to be sporadic, relatives of individuals with MGUS or other plasma cell disorders have an increased risk of developing MGUS and related diseases [26-30]. Studies of the incidence of plasma cell and lymphoproliferative disorders among first-degree relatives of patients with multiple myeloma or MGUS support a shared environmental and/or genetic predisposition to these disorders.
●Using population-based data from Sweden, relatives of MGUS individuals had significantly increased risks for MGUS (relative risk [RR] 2.8), multiple myeloma (RR 2.9), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (RR 4.0), and chronic lymphocytic leukemia (RR 2.0) [27].
●Using a cohort of MGUS individuals from Olmsted County identified through a population-based prevalence study and individuals with myeloma or MGUS from the Mayo Clinic, the risk of MGUS was found to be significantly increased among relatives of those with myeloma (RR 2.0) or MGUS (RR 3.3) [28,29].
●Further support for a genetic predisposition comes from genome-wide association studies and case-control studies that have demonstrated an association between certain relatively common normally occurring variants in genes, called single-nucleotide polymorphisms (SNPs), and an increased incidence of MGUS and myeloma [31-33].
Since there are no proven preventative approaches, there is no role for screening asymptomatic relatives at this time.
Associated conditions — MGUS has been reported in association with several non-malignant disorders, some of them quite rare (table 1) [34]. It is not clear whether these conditions are pathogenetically related or merely represent coincidental associations, given the relatively frequent occurrence of MGUS in the general population above the age of 50.
There is no clear association between MGUS and autoimmune diseases or immune-related conditions. Although several retrospective studies had suggested an increased risk of MGUS among patients with these conditions, a large Icelandic prospective population-based screening study (iStopMM) did not find an association (prevalence ratio 1.05; 95% CI 0.97-1.15) [35]. The increased prevalence in prior retrospective studies likely reflects a sampling bias as testing was likely preferentially performed in this population due to a perceived association.
A population-based study of 17,398 subjects from Olmsted County found a number of previously unreported disease associations with MGUS, including mycobacterial infection and superficial thrombophlebitis [36]. An appendix providing the incidence of each of the 16,062 disease codes in individuals with MGUS and controls, along with relative risks and confidence intervals, is available as supplementary online content. There is also an increased risk of fractures in individuals with MGUS compared with the general population [37].
Rare cases of telangiectasias, erythrocytosis with elevated erythropoietin, MGUS, perinephric fluid collections, and intrapulmonary shunting (TEMPI syndrome) have been reported in the literature, although little is known about the physiological basis of this constellation of symptoms [38-41]. Responses have been reported after administration of therapies used for plasma cell dyscrasias (eg, bortezomib, melphalan-based autologous hematopoietic cell transplantation, and daratumumab), suggesting that these symptoms are at least partially related to the underlying plasma cell dyscrasia [40,42-45].
Of importance, MGUS has been described in approximately one-third of individuals with acquired angioedema (acquired C1 inhibitor deficiency). Laryngeal edema is the most severe and potentially lethal complication of acquired angioedema, which may require urgent treatment with C1 inhibitor concentrate. (See "Acquired C1 inhibitor deficiency: Clinical manifestations, epidemiology, pathogenesis, and diagnosis" and "Acquired C1 inhibitor deficiency: Management and prognosis".)
PRESENTING FEATURES — By definition, individuals with MGUS have no symptoms of myeloma or related malignancy that can be attributable to their monoclonal (M) protein. Most individuals are identified when an M protein is detected as an incidental finding on protein electrophoresis performed as part of an evaluation for one of a wide variety of clinical symptoms and disorders (eg, peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia, elevated erythrocyte sedimentation rate).
Since MGUS is asymptomatic, the condition is likely to have existed in an undetected state for years prior to diagnosis. As an example, a population-based prevalence study of 21,463 individuals from Olmsted County, Minnesota, estimated that more than half of individuals diagnosed with MGUS at age 70 had had an M protein for at least 10 years, and that approximately one-quarter had had an M protein for 20 years [15].
Monoclonal proteins — MGUS (non-IgM and IgM) is characterized by the presence of an M protein produced and secreted by clonal plasma cells, which can be detected by protein electrophoresis of the serum (SPEP) and/or of an aliquot of urine (UPEP) from a 24-hour collection combined with immunofixation of the serum and urine (algorithm 1). Serum free light chain assays can detect low concentrations of monoclonal free light chain in the serum. They can be used to diagnose light-chain MGUS and predict the risk of progression of MGUS. While not widely available, mass spectrometry is used at some centers to identify and classify M proteins in the serum. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Indications and uses'.)
The M protein usually presents as a single narrow peak, like a church spire, in the gamma, beta, or alpha-2 region of the densitometer tracing (figure 1) or as a dense, discrete band on the agarose gel (image 1). Two M proteins are present (biclonal gammopathy) in 2 to 4 percent (figure 2) of individuals with clonal plasma cell disorders. (See "Laboratory methods for analyzing monoclonal proteins".)
Serum immunofixation confirms the presence of an M protein and determines its type (figure 3). The clonal plasma cells can produce immunoglobulin heavy chains plus light chains or light chains alone, with the following approximate frequencies (table 2) [12,23,45,46]:
●IgG – 55 percent
●IgM – 14 percent
●IgA – 9 percent
●IgD – <1 percent
●Biclonal – 3 percent
●Kappa or lambda light chain only (no heavy chain) – 19 percent
•Kappa light chain – 62 percent
•Lambda light chain – 38 percent
The presence of an IgD M protein almost always indicates multiple myeloma, AL amyloid, or plasma cell leukemia, although two cases of IgD MGUS have been reported [3]. IgD M protein is difficult to detect at low concentrations and may evade detection. Of the approximately 0.8 percent of the population age ≥50 that have light chain-MGUS, 74 percent have a kappa light chain predominance [23].
The amount of M protein in MGUS is usually small and by definition less than 3 g/dL (30 g/L) in the serum. In a large population-based study, the concentration of monoclonal immunoglobulin was <1.0 g/dL (10 g/L) in 63.5 percent and ≥2.0 g/dL (20 g/L) in 4.5 percent [12]. Approximately one-third of individuals will have a decrease in the concentration of uninvolved immunoglobulins (eg, IgM and IgA in the case of IgG MGUS) [47,48]. A monoclonal urinary light chain is seen in approximately 20 percent.
Biclonal gammopathy — As noted above, 3 percent of individuals with MGUS had biclonal, rather than monoclonal, gammopathy. Such individuals have the same clinical spectrum as those with monoclonal gammopathy, and should be followed in the same manner [49]. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Biclonal gammopathy'.)
Laboratory artifacts — Circulating M proteins may interfere with one or more laboratory tests performed on liquid-based automated analyzers, either by precipitating during the analysis, or by virtue of their specific binding properties. The most common artifacts are a low value for HDL cholesterol, a high value for bilirubin, as well as altered measurement of inorganic phosphate. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Interference with laboratory tests'.)
Although not a laboratory artifact, M protein can increase the serum viscosity and erythrocyte sedimentation rate (ESR).
Peripheral smear — The complete blood count and peripheral smear are usually normal. Infrequently, rouleaux formation is seen. Rouleaux formation is the phenomenon in which red cells take on the appearance of a stack of coins in diluted suspensions of blood, and is seen in individuals with elevated serum protein levels (picture 1). The presence of circulating plasma cells of the same isotype in the peripheral blood, as detected using a slide-based immunofluorescence assay or flow cytometry, is more commonly seen with active MM, but can also be seen in some individuals with MGUS [50,51]. (See "Evaluation of the peripheral blood smear", section on 'Initial approach'.)
Bone marrow examination — A bone marrow aspirate and biopsy must demonstrate fewer than 10 percent clonal plasma cells, or in the case of IgM MGUS, fewer than 10 percent infiltration by clonal lymphoplasmacytic cells. (See "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma", section on 'Bone marrow'.)
Conventional cytogenetics are normal in individuals with MGUS because of the low proliferative rate and small number of plasma cells within the bone marrow samples. However, studies using more sensitive methods have shown that chromosomal abnormalities are very common in MGUS [52].
●Results obtained by interphase fluorescence in situ hybridization (FISH) demonstrate chromosomal aneuploidy (especially hyperdiploidy) in approximately 50 percent of individuals with MGUS [53-55].
●Translocations affecting the immunoglobulin heavy chain (IgH) locus on chromosome 14q32 and five key partner chromosomes have been observed in the remaining 50 percent of individuals with MGUS. These include: t(11;14) affecting the cyclin D1 gene, t(4;14) affecting the FGFR-3 and MMSET genes, t(6;14) affecting the cyclin D3 gene, t(14;16) affecting the cmaf gene, and t(14;20) affecting the mafB gene [56,57]. These five translocations are termed "primary" IgH translocations. (See "Multiple myeloma: Pathobiology", section on 'Immunoglobulin heavy chain translocations'.)
Chromosomal abnormalities detected by FISH, including hyperdiploidy, IgH translocations, and deletion of chromosome 13 are not used to differentiate MGUS from multiple myeloma. The specific abnormalities that might indicate a high rate of progression from MGUS to multiple myeloma have not yet been reliably identified [52,54,58].
DIAGNOSIS
Screening — Universal screening of asymptomatic individuals of any age for monoclonal gammopathy is not recommended [59]. Such screening would be associated with high costs for payers and undue emotional burden on individuals with a low risk of progressing to a symptomatic disorder. However, screening can be considered in individuals over the age of 50 with two or more affected first-degree relatives with multiple myeloma or related disorder [60]. (See "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Disease progression'.)
Evaluation
Initial testing for all — The diagnosis of MGUS is usually incidental when a monoclonal (M) protein <3 g/dL (30 g/L) is found as part of the evaluation of another disorder, such as unexplained age-inappropriate bone loss, unexplained proteinuria, an elevated total protein in the blood, or peripheral neuropathy without a defined etiology (algorithm 1) [59].
At a minimum, individuals suspected of having MGUS should be evaluated with the following studies:
●Complete blood count
●Serum calcium and creatinine
●Serum protein electrophoresis and immunofixation
●Serum free light chain (FLC) assay
●Quantitative immunoglobulins
The serum FLC assay can be used initially in place of urine studies. However, if an M protein is seen on serum studies or if the serum FLC ratio is abnormal, urine studies need to be performed.
Urine studies usually include routine urinalysis and 24-hour urine collection with electrophoresis and immunofixation. Routine dipstick of the urine for protein is not sufficient. The dipstick primarily detects albumin, the excretion of which is typically increased in individuals with amyloidosis involving the kidney, but the dipstick test often does not detect immunoglobulin light chains. Alternatively, one could perform protein electrophoresis and immunofixation on a single voided urine specimen. A 24-hour collection to quantitate urinary protein excretion would be necessary only if the "spot test" result is positive. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Detection and measurement of total urinary protein excretion' and "Patient education: Collection of a 24-hour urine specimen (Beyond the Basics)".)
While not widely available, mass spectrometry is being used for identification of M proteins at some centers. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Mass spectrometry'.)
Cross-sectional imaging — Imaging is indicated for a subset of individuals to evaluate for multiple myeloma. We suggest whole body low dose computed tomography (CT) without contrast or whole-body magnetic resonance imaging (MRI) for most individuals with MGUS. These modalities are more sensitive than plain radiographs for the detection of most skeletal lesions in myeloma. Imaging in myeloma is discussed separately (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Imaging'.)
Imaging may be omitted in individuals without anemia, hypercalcemia, and kidney impairment who have one of the following low-risk scenarios [61-63]:
●IgG monoclonal protein <1.5 g/dL (15 g/L) and a normal serum FLC ratio
●Light chain only monoclonal protein with serum FLC ratio <8
●IgM monoclonal protein with no clinical concern for bone lesions or myeloma
Such individuals have a low risk of multiple myeloma or Waldenstrom macroglobulinemia requiring therapy.
Bone marrow aspiration and biopsy — A bone marrow aspiration and biopsy is indicated in all individuals with evidence of a monoclonal protein and any of the following:
●Anemia (hemoglobin <10 g/dL or 2 g/dL below normal)
●Kidney impairment (serum creatinine >2 mg/dL [176.8 micromol/liter])
●Elevated serum calcium (serum calcium >11.5 mg/dL [2.875 mmol/liter])
●Abnormalities on imaging
It is also indicated for most individuals with an M protein ≥1.5 g/dL (15 g/L), individuals with IgA MGUS of any size, and most individuals with an abnormal serum FLC ratio.
Bone marrow evaluation can be deferred in individuals with no evidence of anemia, lymphadenopathy, or organomegaly with the following low-risk scenarios [6,60,62]:
●IgG monoclonal protein <1.5 g/dL (15 g/L) with normal FLC ratio
●Light chain only monoclonal protein with FLC ratio <8
●IgM monoclonal protein <1.5 g/dL (15 g/L)
●<10 percent bone marrow involvement estimated by iStopMM risk model
Bone marrow may also be deferred in older asymptomatic adults or in frail older adults with limited life expectancy in whom myeloma or a related malignancy is considered unlikely, who can be safely followed.
Omission of the bone marrow evaluation in individuals with IgG-type MGUS with serum M protein <1.5 g/dL (15 g/L), a normal serum FLC ratio, and with no bone pain or clinical concern for myeloma is supported by a study of 1271 individuals with MGUS or multiple myeloma with minimal bone pain (grade 0/1) whose initial workup included bone marrow evaluation and skeletal survey (without serum FLC analysis) with the following results [62]:
●Among individuals with an M protein ≤1.5 g/dL (15 g/L), the percentage of individuals with bone marrow plasma cell infiltration >10 percent was 7.3 percent overall but ranged from 4.7 percent to 20 percent in those with IgG and IgA isotypes, respectively.
●For those with an IgG M protein <0.5 g/dL (5 g/L), <1 percent had bone marrow plasma cell infiltration >10 percent by morphology.
●Similarly, among those with an IgG M protein ≤1.5 g/dL (15 g/L), the percentage of individuals with bone lesions on skeletal survey was <2 percent.
The iStopMM risk model has been proposed as an alternative method of estimating the risk of bone marrow involvement. This multivariate model was developed using data from >1000 persons included in the iStopMM prospective Icelandic population-based screening study who underwent bone marrow aspiration and biopsy as part of a planned follow-up strategy for monoclonal gammopathy [64]. It excluded participants who had features suggestive of multiple myeloma (eg, anemia, kidney impairment, hypercalcemia, or bone lesions). The model incorporates the following factors:
●MGUS isotype (IgG, IgA, biclonal)
●M-protein concentration
●FLC ratio
●Total concentrations of IgG, IgA, and IgM
Approximately 15 percent of the cohort had bone marrow biopsy results consistent with smoldering MM (SMM) or MM (≥10 percent bone marrow plasma cells). When the model was used to identify those with a ≥10 percent risk for SMM or MM, the sensitivity and specificity were 86 and 67 percent, respectively. In this population, the model had a 96 percent negative predictive value. If it were used to defer bone marrow sampling for those estimated to have <10 percent bone marrow involvement, it would allow 59 percent of the population to defer bone marrow, of whom 3.6 percent would have SMM and none would have MM upon biopsy. A comparison with the Mayo Clinic model in this population suggested that the iStopMM model would allow more participants to avoid unnecessary bone marrow sampling. The Mayo Clinic model recommends deferring a bone marrow evaluation in persons with low-risk MGUS and defines low-risk MGUS as IgG MGUS with monoclonal protein <1.5 gm/dL and normal FLC ratio. The iStopMM model uses entry of actual numeric values into the risk calculator. Positive and negative predictive values are directly related to the prevalence of disease in a population. If all other things are equal, negative predictive values decrease with increasing prevalence, whereas positive predictive values increase with increasing prevalence.
Further details on risk stratification of individuals with MGUS and expected clinical course are discussed separately. (See "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Risk stratification to estimate risk of progression'.)
Diagnostic criteria
Non-IgM MGUS — Non-IgM MGUS (IgG, IgA, or IgD MGUS) is diagnosed by meeting the following three criteria (algorithm 1) [1,65,66]:
●The presence of a serum M protein (whether IgA, IgG, or IgD), at a concentration <3 g/dL (<30 g/L). The M protein is detected with serum protein electrophoresis followed by immunofixation for the identification of the M protein type (figure 1 and figure 3) [67]. It must be distinguished from a polyclonal gammopathy (figure 4). (See "Laboratory methods for analyzing monoclonal proteins".)
●Fewer than 10 percent clonal plasma cells in the bone marrow.
●The absence of lytic bone lesions, anemia, hypercalcemia, and kidney impairment related to the plasma cell proliferative process.
Note that serum involved/uninvolved FLC ratio is almost always <100, and if it is ≥100, care must be taken to fully evaluate, including bone marrow and imaging, to rule out myeloma.
IgM MGUS — IgM MGUS is diagnosed by meeting the following three criteria (algorithm 1) [1,65,66]:
●The presence of a serum IgM M protein at a concentration <3 g/dL (<30 g/L). The M protein is detected with serum protein electrophoresis followed by immunofixation for the identification of the M protein type (figure 1 and figure 3) [67]. It must be distinguished from a polyclonal gammopathy (figure 4). (See "Laboratory methods for analyzing monoclonal proteins".)
●Fewer than 10 percent clonal lymphoplasmacytic/plasma cells in the bone marrow.
●The absence of end-organ damage such as anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly related to the plasma cell proliferative process. These individuals must then be followed [68]. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Clinical presentation'.)
Note that serum involved/uninvolved FLC ratio is almost always <100, and if it is ≥100, care must be taken to fully evaluate, including bone marrow and imaging, to rule out myeloma.
Light chain MGUS — Light chain MGUS (LC-MGUS) is diagnosed by meeting the following criteria (algorithm 1) [1,23]:
●The presence of an abnormal FLC ratio.
●Increased level of the appropriate involved light chain (eg, increased kappa FLC in individuals with a high ratio and increased lambda FLC in individuals with a low ratio).
●No monoclonal immunoglobulin heavy chain (IgG, IgA, IgD, or IgM).
●Fewer than 10 percent clonal plasma cells in the bone marrow.
●The absence of lytic bone lesions, anemia, hypercalcemia, and kidney impairment related to the plasma cell proliferative process.
Note that serum involved/uninvolved FLC ratio is almost always <100, and if it is ≥100, care must be taken to fully evaluate, including bone marrow and imaging, to rule out myeloma.
When interpreting the FLC assay in clinical practice, clinicians should refer to the normal reference range specified by the laboratory reporting the result. Reference ranges differ between assays from different manufacturers and are dependent upon the instrument used for measurement. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Serum free light chains'.)
FLC concentration is affected by kidney function and the reference intervals used for the FLC ratio (and FLC level) should be adjusted for the estimated glomerular filtration rate (eGFR) [69,70]; for the serum FLC assay developed by The Binding Site:
●eGFR ≥60 mL/min/1.73 m2
•FLC ratio 0.26 to 1.65
•Serum free kappa 3.3 to 19.4 mg/L
•Serum free lambda 5.7 to 26.3 mg/L
●eGFR 45 to 59 mL/min/1.73 m2
•FLC ratio 0.46 to 2.62
•Serum free kappa 7.8 to 83.6 mg/L
•Serum free lambda 7.3 to 65.1 mg/L
●eGFR 30 to 44 mL/min/1.73 m2
•FLC ratio 0.48 to 3.38
•Serum free kappa 8.8 to 103.3 mg/L
•Serum free lambda 8.2 to 73.2 mg/L
●eGFR <30 mL/min/1.73 m2
•FLC ratio 0.54 to 3.30
•Serum free kappa 11.7 to 265 mg/L
•Serum free lambda 12.6 to 150.9 mg/L
Subjects with an abnormal FLC ratio and no expression of an immunoglobulin heavy chain, but without an increased concentration of the involved light chain, are not considered to have LC-MGUS. Instead, abnormal FLC ratios in these individuals likely reflect kidney impairment or polyclonal activation. (See "Laboratory methods for analyzing monoclonal proteins", section on 'Use in patients with kidney impairment'.)
DIFFERENTIAL DIAGNOSIS — It is important to distinguish MGUS from more advanced plasma cell dyscrasias for the purposes of prognosis and treatment. The main conditions to consider in the differential diagnosis of MGUS are multiple myeloma (smoldering or symptomatic), Waldenström macroglobulinemia (smoldering or symptomatic), idiopathic Bence Jones proteinuria, and primary amyloidosis (AL) (table 3).
Multiple myeloma — Both MGUS and multiple myeloma (MM) are characterized by a monoclonal (M) protein in the serum (IgG, IgA, or IgD; kappa or lambda) or in the urine (kappa or lambda) that is produced by a clonal population of plasma cells in the bone marrow. A subset of individuals with MGUS will progress to smoldering (asymptomatic) MM and then to symptomatic MM. It is impossible to differentiate MGUS from those who subsequently develop smoldering or symptomatic MM at the time of initial presentation.
By definition, any individual with a non-IgM serum M protein ≥3 g/dL (30 g/L), with a serum involved/uninvolved free light chain (FLC) ratio ≥100, or with ≥10 percent clonal plasma cells in the bone marrow does not have MGUS (table 4). In such a case, a diagnosis of MM or smoldering MM (SMM) should be made. The morphologic appearance of the plasma cells in the bone marrow is of little help unless the cells have plasmablastic morphologic features (eg, nucleoli), which favors the diagnosis of MM [71]. However, due to patchy bone marrow involvement, approximately 4 percent of individuals with MM will have a bone marrow aspirate and biopsy demonstrating less than 10 percent clonal plasma cells [72].
While the diagnosis of MGUS requires the absence of anemia, hypercalcemia, kidney impairment, and lytic bone lesions related to the plasma cell proliferative disorder, the mere presence of one or more of these features in conjunction with an M protein does not automatically indicate MM or related malignancy, since these abnormalities may be due to unrelated coexisting diseases. As an example, individuals with MGUS may have anemia related to nutritional deficiency; kidney impairment related to coexisting diabetes or hypertension; hypercalcemia due to hyperparathyroidism; or lytic bone lesions from metastatic carcinoma. Only individuals in whom these clinical findings of end organ damage are felt to be clearly related to the plasma cell disorder are considered to have MM. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
●The presence of osteolytic lesions and unexplained hypercalcemia strongly suggests MM, but metastatic carcinoma must be excluded.
●Similarly, unexplained kidney impairment suggests possible involvement by the light chains due to MGUS, MM, or a related malignancy. If kidney impairment is not accompanied by significant light chain excretion or other features of MM, a kidney biopsy may be needed to ascertain that the kidney impairment is caused by the plasma cell proliferative process [73]. (See "The kidney biopsy" and "Diagnosis and treatment of monoclonal gammopathy of renal significance".)
Other laboratory determinations, such as a low CD4 cell count, chromosomal abnormalities with FISH analysis (eg, deletion 13), the presence of J chains in plasma cells, and elevated plasma cell acid phosphatase levels are all unreliable for differentiation of MGUS and MM. More sophisticated techniques of differentiating MGUS from MM (eg, plasma cell labeling index, serum concentration of interleukin [IL]-6, gene expression profiling) are not used in routine clinical practice [50,51,74-78]. However, a clearly elevated level of beta-2 microglobulin in the absence of kidney failure and/or an inflammatory process would suggest a diagnosis of MM, and the individual should be carefully evaluated for this possibility.
If there are doubts about the differentiation of MGUS and SMM from MM, and whether to begin chemotherapy immediately, one should withhold treatment and re-evaluate in two or three months. (See "Multiple myeloma: Overview of management".)
Smoldering multiple myeloma — Smoldering multiple myeloma (SMM), also called asymptomatic MM, is an intermediate stage between MGUS and symptomatic MM. SMM is diagnosed in individuals who meet the following criteria (table 5 and table 4) [66,79,80]:
●Serum M protein ≥3 g/dL (30 g/L) and/or ≥10 to <60 percent bone marrow clonal plasma cells.
●Absence of lytic lesions, anemia, hypercalcemia, and kidney impairment (end-organ damage) attributable to the underlying plasma cell proliferation.
SMM is distinguished from MGUS based on the size of the M protein and the percent plasma cells in the bone marrow. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Smoldering multiple myeloma'.)
SMM is distinguished from MM based on the absence or presence of end-organ damage (hypercalcemia, anemia, bone lesions, kidney impairment) that is thought to be related to the underlying plasma cell disorder.
Individuals with SMM should have less than 60 percent bone marrow clonal plasma cells. Individuals who have 60 percent or more clonal bone marrow plasma cells rarely present without end-organ damage attributable to the plasma cell disorder, and even if they do present as such, they almost inevitably progress to overt MM within two years (median time to progression is seven months) [81]. Therefore, such individuals are best considered as having MM even in the absence of end-organ damage. Similarly, individuals with serum involved/uninvolved free light chain (FLC) ratio of 100 or more, and those with >1 focal lesion on magnetic resonance imaging have a rate of progression within the first two years that is high enough to justify systemic therapy.
Light chain smoldering multiple myeloma (Idiopathic Bence Jones proteinuria) — Monoclonal light chains can be found in the urine (Bence Jones proteinuria) if their production exceeds the rate of light chain re-absorption in the kidneys (figure 5 and figure 6) [82]. FLCs are present in a subset of individuals with MM, AL amyloidosis, and WM; in MM and AL amyloidosis they may be present with or without an associated heavy chain component. Light chain smoldering multiple myeloma (LC-SMM) is an intermediate stage between light chain MGUS and light chain MM characterized by the presence of monoclonal FLCs without any detectable heavy chain component (eg, IgG, IgA, IgM) [2].
To make a diagnosis of LC-SMM, the following criteria must be met [2]:
●Monoclonal light chains in the urine (Bence Jones proteinuria) with a level ≥0.5 g/24 hours or associated with ≥10 to 60 percent bone marrow plasma cells, or both.
●No immunoglobulin heavy chain expression in the serum or urine.
●No lytic bone lesions, hypercalcemia, anemia, kidney impairment or other myeloma-defining events, WM, or AL amyloidosis.
Note that serum involved/uninvolved FLC ratio is almost always <100, and if it is ≥100, care must be taken to fully evaluate, including bone marrow and imaging, to rule out myeloma. Elevation of serum involved FLC ratio ≥100 with bone marrow plasma cell involvement ≥10 percent indicates myeloma.
Secondary MGUS — Secondary MGUS refers to the development of a new M protein during the course of MM that has an isotype (heavy and/or light chain) distinct from the original clone (eg, IgM MGUS in an individual with IgG MM). In a series of 1942 patients with MM, secondary MGUS developed in 128 (6.6 percent) at a median of 12 months from the diagnosis of myeloma [83]. More than one isotype occurred in approximately 30 percent of patients. Secondary MGUS was much more common among patients who had undergone hematopoietic cell transplantation and was associated with superior survival in this study. The additional M protein that occurs following transplantation commonly resolved without treatment with a median duration of approximately six months.
Waldenström macroglobulinemia — Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity demonstrating lymphoplasmacytic lymphoma (LPL) in the bone marrow with an IgM monoclonal gammopathy in the blood. Unlike individuals with IgM MGUS who are asymptomatic, patients with WM may present with symptoms related to the infiltration of the hematopoietic tissues or the effects of monoclonal IgM in the blood. Symptoms of hyperviscosity and the presence of lymphadenopathy and/or splenomegaly favor a diagnosis of WM. There is a greater probability of an abnormal FLC ratio in WM compared with IgM MGUS. In one study, an abnormal kappa/lambda serum FLC ratio was found in 76 and 24 percent of those with WM and IgM MGUS, respectively [84]. Abnormalities in MYD88 can be seen in both WM and IgM MGUS [85,86]. Smoldering WM is considered an intermediate entity between IgM MGUS and WM, which fits the diagnostic criteria for WM but has not yet resulted in symptoms. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia" and "Clinical manifestations, pathologic features, and diagnosis of lymphoplasmacytic lymphoma".)
To make a diagnosis of WM (smoldering or symptomatic), the following criteria must be met [87]:
●An IgM monoclonal gammopathy (of any size) must be present in the serum.
●Ten percent or more of the bone marrow biopsy sample must demonstrate infiltration by LPL.
Individuals without end-organ damage such as anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly related to the lymphoplasmacytic cell proliferative process are considered to have smoldering WM and must be followed closely [68]. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Clinical presentation'.)
AL amyloidosis and light chain deposition disease — Primary (amyloid light chain) amyloidosis and light chain deposition disease are plasma cell or, less commonly, B cell proliferative disorders associated with the pathologic deposition of monoclonal light chains. In primary (AL) amyloidosis, there is deposition of linear non-branching fibrils that are derived from monoclonal immunoglobulin light chains. The deposition of these fibrils within organs can produce the nephrotic syndrome, heart failure, hepatomegaly, vascular fragility and abnormal coagulation times with associated excess bruising, and other findings that are not seen in MGUS.
In light chain deposition disease, there is deposition of intact monoclonal immunoglobulin light chains commonly in the kidney resulting in nephrotic syndrome. Like AL amyloidosis, light chain deposition disease can affect other organs including the heart and liver. (See "Monoclonal immunoglobulin deposition disease" and "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis".)
As noted above, the diagnosis of MGUS requires the absence of anemia, hypercalcemia, kidney impairment, and lytic bone lesions related to the plasma cell proliferative disorder. However, the presence of kidney impairment in conjunction with an M protein does not automatically indicate AL amyloidosis or other pathologic process related to the underlying dysproteinemia, since these abnormalities may be unrelated (eg, MGUS in an individual with kidney impairment secondary to diabetic or hypertensive nephropathy).
The diagnosis of primary AL amyloidosis is initially suspected from typical clinical findings (eg, macroglossia, neuropathy, periorbital purpura, nephrotic range proteinuria, restrictive cardiomyopathy, in conjunction with a serum or urinary M protein) and is confirmed by demonstrating the following two features:
●The presence of amyloid deposition on biopsy of the abdominal fat pad, bone marrow, rectum, or, if necessary, the involved organ (eg, kidney, liver, sural nerve), plus
●Evidence of a clonal plasma cell proliferative disorder, or less commonly a clonal B cell disorder.
POEMS syndrome — POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) is characterized by the presence of a monoclonal plasma cell disorder, peripheral neuropathy, and more than one of the following features: osteosclerotic myeloma, Castleman disease (angiofollicular lymph node hyperplasia), increased levels of serum vascular endothelial growth factor (VEGF), organomegaly, endocrinopathy, edema, typical skin changes, and papilledema. POEMS syndrome can be distinguished from MGUS using the diagnostic criteria shown in the table (table 6). (See "POEMS syndrome".)
CLINICAL COURSE AND MANAGEMENT — Each of the three distinct clinical types of MGUS has a small risk of progressing to a unique intermediate (more advanced) premalignant stage and to a malignant plasma cell dyscrasia or lymphoproliferative disorder. Individuals with MGUS should be monitored for disease progression and for potential complications. This is presented in more detail separately. (See "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Monitoring for progression'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Monoclonal gammopathy of undetermined significance".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Monoclonal gammopathy of undetermined significance (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition and epidemiology – Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. MGUS occurs in over 3 percent of the general White population over the age of 50 and is typically detected as an incidental finding when individuals undergo a protein electrophoresis as part of an evaluation for a wide variety of clinical symptoms and disorders. (See 'Epidemiology' above.)
●Subtypes of MGUS – There are three distinct clinical types of MGUS, each with a risk of progressing through a unique intermediate (more advanced) premalignant stage and then to a malignant plasma cell dyscrasia or lymphoproliferative disorder (see "Clinical course and management of monoclonal gammopathy of undetermined significance", section on 'Disease progression'):
•Non-IgM MGUS (IgG, IgA, or IgD MGUS) is the most common type of MGUS and has the potential to progress to smoldering (asymptomatic) multiple myeloma and to symptomatic multiple myeloma. Less frequently, these individuals progress to AL amyloidosis, light chain deposition disease, or another lymphoproliferative disorder.
•IgM MGUS accounts for approximately 15 percent of MGUS cases. It is considered separately from the non-IgM MGUS because it has the potential to progress to smoldering or active Waldenström macroglobulinemia. Infrequently, IgM MGUS can progress to IgM multiple myeloma or AL amyloidosis.
•Light chain MGUS may progress to idiopathic Bence Jones proteinuria and to light chain multiple myeloma, AL amyloidosis, or light chain deposition disease.
●When to suspect MGUS – The presence of MGUS is suspected in an asymptomatic individual in whom a serum monoclonal immunoglobulin has been detected in a concentration of <3 g/dL (30 g/L). (See 'Epidemiology' above.)
●Initial evaluation of suspected cases – At a minimum, individuals suspected of having MGUS should be evaluated with the following studies (algorithm 1) (see 'Initial testing for all' above):
•Complete blood count
•Serum calcium and creatinine
•Serum protein electrophoresis (SPEP) and immunofixation
•Serum free light chain (FLC) assay
•Quantitation of immunoglobulins
The serum FLC assay can be used initially in place of urine studies. However, if a monoclonal (M) protein is seen on serum studies or if the serum FLC ratio is abnormal, urine electrophoresis and immunofixation need to be performed.
●Imaging and bone marrow evaluation – Cross-sectional imaging (eg, whole body low dose computed tomography without contrast) and bone marrow aspiration and biopsy are indicated for many individuals with a monoclonal protein (algorithm 1). (See 'Cross-sectional imaging' above.)
Imaging may be omitted based on the discretion of the treating physician in individuals without anemia, hypercalcemia, and kidney impairment and any of the following:
•IgG monoclonal protein <1.5 g/dL (15 g/L) and a normal serum FLC ratio
•Light chain only monoclonal protein with serum FLC ratio <8
•IgM monoclonal protein with no clinical concern for bone lesions or myeloma
Bone marrow evaluation may be omitted based on the discretion of the treating physician in individuals with no evidence of anemia, hypercalcemia, kidney impairment, lymphadenopathy, or organomegaly and any of the following:
•IgG monoclonal protein <1.5 g/dL (15 g/L) with normal FLC ratio
•Light chain only monoclonal protein with FLC ratio <8
•IgM monoclonal protein <1.5 g/dL (15 g/L)
•<10 percent bone marrow involvement estimated by iStopMM risk model
●Diagnostic criteria – The diagnosis of MGUS (non-IgM and IgM) is confirmed when the following criteria have been met (table 5) (see 'Diagnostic criteria' above):
•The presence of a serum M protein (whether IgA, IgG, or IgM), at a concentration <3 g/dL (30 g/L) detected with SPEP and immunofixation.
•Involved/uninvolved FLC ratio <100.
•Fewer than 10 percent plasma cells in the bone marrow (if indicated).
•The absence of lytic bone lesions, anemia, hypercalcemia, and kidney impairment or other myeloma-defining events related to the plasma cell proliferative process.
•Individuals should not have leukocytosis, abnormal circulating cells, lymphadenopathy, hepatomegaly, splenomegaly, or undiagnosed mass lesions that can be attributed to a clonal plasma cell or lymphoproliferative disorder.
●Differential diagnosis – MGUS must be differentiated from diseases that also present with a monoclonal gammopathy. These include multiple myeloma (smoldering or symptomatic), Waldenström macroglobulinemia (smoldering or symptomatic), light chain smoldering multiple myeloma (idiopathic Bence Jones proteinuria), and primary amyloidosis (AL) (table 4 and table 3 and table 5). (See 'Differential diagnosis' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Robert A Kyle, MD, who made extensive contributions to earlier versions of this topic review.
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