Author:S Vincent Rajkumar, MDSection Editor:Robert A Kyle, MDDeputy Editor:Rebecca F Connor,

MD
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All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2018. | This topic last updated: Sep 06, 2018.
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, renal insufficiency, hyperviscosity) related to the proliferative process.

MGUS occurs in over 3 percent of the general Caucasian population over the age of 50 and is typically
detected as an incidental finding when patients 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 patients 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
monoclonal 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 generic term MGUS used in most studies only includes patients with non-IgM MGUS and IgM
MGUS; LC-MGUS is a newly defined entity. The diagnosis of patients with MGUS will be discussed
here [3-6]. The management of patients with MGUS, the recognition of serum or urinary monoclonal
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" and "Laboratory methods for
analyzing monoclonal proteins" and "Clinical features, laboratory manifestations, and diagnosis of
multiple myeloma" and "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of
Waldenström macroglobulinemia" and "Pathogenesis of immunoglobulin light chain (AL) amyloidosis
and light and heavy chain deposition diseases".)

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 patients are diagnosed before the age of 40 [12,13]. The incidence and prevalence rises with
patient age [12,14,15], is higher in men than women [12], and is two- to threefold higher in Africans and
African Americans compared with Caucasians [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].

The prevalence of MGUS among a well-defined, largely Caucasian 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 persons ≥50, ≥70, and ≥85 years of age was 3.2, 5.3, and 7.5 percent,
respectively.

●Age-adjusted rates for persons ≥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 persons over age 50 was
0.8 and 3.4 percent, respectively [21].

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
American Blacks was also seen in a large study of inpatients from United States Veterans Affairs
hospitals [18] and a large population-based study of Southern women [22]. The latter study also showed
that the increased risk of MGUS seen in African 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 Blacks is likely related to shared genetics, rather than environmental
factors [19,22].

There is a paucity of information regarding the incidence in other races. A study in adult Asians from
Japan that used an older method for screening suggests that Japanese persons may have a slightly lower
incidence than that seen in Caucasians from Minnesota [11]. The limited data available also suggest that
the prevalence of MGUS in Mexicans is less than in Caucasians from Minnesota [23].

Genetic predisposition — While most cases of MGUS appear to be sporadic, relatives of persons with
MGUS have an increased risk of developing MGUS and related diseases [24]. 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 patients 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) [25].
●Using a cohort of MGUS patients from Olmsted County identified through a population-based
prevalence study and patients 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)
[26,27].

●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 [28-30].

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) [31], and also has been reported along with autoimmune disorders such
as systemic lupus erythematosus and immune thrombocytopenia (ITP) [32,33]. 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.

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 [34]. An appendix providing the incidence of each of the 16,062 disease codes in
patients 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 patients with MGUS
compared with the general population [35].

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 [36-38].
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 [38-
42].

Of importance, MGUS has been described in approximately one-third of patients 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, patients with MGUS have no symptoms of myeloma or

related malignancy that can be attributable to their monoclonal protein. Most patients are identified when
a monoclonal 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 persons from Olmsted
County, Minnesota, estimated that more than half of men and women diagnosed with MGUS at age 70
had had a monoclonal protein for at least 10 years, and that approximately one-quarter had had a
monoclonal protein for 20 years [15].
Monoclonal proteins — MGUS (non-IgM and IgM) is characterized by the presence of a monoclonal
(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. (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 patients 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 frequencies (table 2) [12,42,43]:

●IgG – 69 percent

●IgM – 17 percent

●IgA – 11 percent

●IgD – <1 percent

●Biclonal – 3 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]. Of the approximately 0.8 percent of
the population age ≥50 that have light chain-MGUS, 74 percent have a kappa light chain predominance
[21].

The amount of monoclonal protein in MGUS is usually small and by definition less than 3 g/dL in the
serum. In a large population-based study, the concentration of monoclonal immunoglobulin was <1.0
g/dL in 63.5 percent and ≥2.0 g/dL in 4.5 percent [12]. Approximately one-third of patients will have a
decrease in the concentration of uninvolved immunoglobulins (eg, IgM and IgA in the case of IgG
MGUS), and many demonstrate a reduction in normal polyclonal or background immunoglobulins
[44,45]. A monoclonal urinary light chain is seen in approximately 20 percent.

Biclonal gammopathy — As noted above, 3 percent of patients with MGUS had biclonal, rather than
monoclonal, gammopathy. Such patients have the same clinical spectrum as those with monoclonal
gammopathy, and should be followed in the same manner [46]. (See "Laboratory methods for analyzing
monoclonal proteins", section on 'Biclonal gammopathy'.)

Laboratory artifacts — Circulating monoclonal 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, monoclonal 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 patients 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 patients with MGUS [47,48]. (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 features, laboratory manifestations, and diagnosis of multiple
myeloma", section on 'Bone marrow examination' and "Clinical manifestations, pathologic features, and
diagnosis of lymphoplasmacytic lymphoma", section on 'Bone marrow'.)

Conventional cytogenetics are normal in patients 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 [49].

●Results obtained by interphase fluorescence in situ hybridization (FISH) demonstrate chromosomal

aneuploidy (especially hyperdiploidy) in approximately 50 percent of patients with MGUS [50-52].

●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 patients 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
[53,54]. These five translocations are termed "primary" IgH translocations. (See "Pathobiology of
multiple myeloma", 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 [49,51,55].

DIAGNOSIS

Screening — There is no role for screening of asymptomatic patients of any age for monoclonal
gammopathy [56]. Such screening would be associated with high costs for payers and undue emotional
burden on persons with a low risk of progressing to a symptomatic disorder. (See "Clinical course and
management of monoclonal gammopathy of undetermined significance", section on 'Disease
progression'.)

Evaluation — The diagnosis of MGUS is usually incidental when a monoclonal protein <3 g/dL 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) [56].

At a minimum, patients suspected of having MGUS should be evaluated with the following studies:

●Complete blood count

●Serum calcium and creatinine

●Serum protein electrophoresis and immunofixation

●Urine protein electrophoresis and immunofixation – The serum free light chain (FLC) assay can be used
initially in place of urine studies. However, if a monoclonal protein is seen on serum studies or if the
serum FLC ratio is abnormal, urine electrophoresis and immunofixation need to be performed.

●Serum FLC assay

●Quantitation of immunoglobulins

●Imaging – A metastatic bone survey is necessary for most patients with MGUS. This skeletal survey
may be omitted in patients with low-risk MGUS (ie, IgG-type MGUS with serum M-protein <1.5 g/dL
and a normal serum FLC ratio) and in patients with IgM MGUS with no clinical concern for bone lesions
or myeloma [57,58]. Cross sectional imaging is preferred if there is clinical concern for multiple
myeloma. (See "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma", section
on 'Imaging'.)

Evaluation of the urine is usually performed using 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 renal amyloidosis, 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)".)

A bone marrow aspiration and biopsy is indicated in all patients with an M-protein ≥1.5 g/dL, patients
with IgA MGUS of any size, patients with an abnormal serum FLC ratio (ie, ratio of kappa to lambda
FLCs <0.26 or >1.65), and in all patients who have any abnormalities of the complete blood count, serum
creatinine, serum calcium, or radiographic bone survey. This practice is supported by a study of 1271
patients 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 [58]:

●Among patients with an M-protein ≤1.5 g/dL, the percentage of patients 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, <1 percent had bone marrow plasma cell infiltration >10
percent by morphology.
●Similarly, among those with an M-protein ≤1.5 g/dL, the percentage of patients with bone lesions on
skeletal survey was <2 percent, irrespective of isotype.

These results support the omission of the bone marrow evaluation in patients with IgG-type MGUS with
serum M-protein <1.5 g/dL, a normal serum FLC ratio, and with no bone pain or clinical concern for
myeloma [6]. 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. Although data are not available to support this approach, we also often defer a bone
marrow biopsy in patients with IgM MGUS with a small M-protein (<1.5 g/dL), normal serum FLC ratio,
with no evidence of anemia, lymphadenopathy, or organomegaly. (See "Clinical course and management
of monoclonal gammopathy of undetermined significance", section on 'Risk stratification'.)

Computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography
(PET) are more sensitive than plain radiographs at detecting bone involvement by multiple myeloma;
however, the clinical importance of asymptomatic bone lesions detected by these imaging modalities
alone is not clear. For patients with non-IgM MGUS, we reserve CT, MRI, and PET/CT for select
patients such as those with bone pain without an abnormality on skeletal survey [59]. CT scan of the chest
and abdomen at the time of diagnosis to evaluate for the possibility of Waldenström macroglobulinemia
should be considered in patients with an IgM monoclonal protein in whom there is clinical suspicion for
hepatosplenomegaly or lymphadenopathy (including patients with unexplained anemia or relatively high
M-protein concentration >2 to 3 g/dL) [4]. Lymphadenopathy in the setting of an IgM monoclonal protein
is suggestive of Waldenström macroglobulinemia. (See "Epidemiology, pathogenesis, clinical
manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Diagnosis'.)

Diagnostic criteria

Non-IgM MGUS — Non-IgM MGUS (IgG, IgA, or IgD MGUS) is diagnosed by meeting the following
three criteria (algorithm 1) [1,60,61]:

●The presence of a serum monoclonal protein (M-protein, whether IgA, IgG, or IgD), at a concentration
<3 g/dL. 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) [62]. 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 renal insufficiency related to the plasma
cell proliferative process. A skeletal survey is adequate to assess the presence of bone lesions if MGUS is
suspected. However, if other imaging studies (such as an MRI, CT, or PET/CT) are done, they should
demonstrate no evidence of bone lesions that can be attributed to the plasma cell disorder.

IgM MGUS — IgM MGUS is diagnosed by meeting the following three criteria (algorithm 1) [1,60,61]:

●The presence of a serum IgM monoclonal protein at a concentration <3 g/dL. 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) [62]. 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 patients
must then be followed [63]. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of
Waldenström macroglobulinemia", section on 'Clinical presentation'.)

Light chain MGUS — Light chain MGUS (LC-MGUS) is diagnosed by meeting the following three
criteria (algorithm 1) [1,21]:

●The presence of an abnormal FLC ratio (ie, ratio of kappa to lambda FLCs <0.26 or >1.65)

●Increased level of the appropriate involved light chain (eg, increased kappa FLC in patients with a ratio
>1.65 and increased lambda FLC in patients with a ratio <0.26)

●No monoclonal immunoglobulin heavy chain (IgG, IgA, IgD, or IgM)

●Fewer than 10 percent clonal lymphoplasmacytic cells in the bone marrow

●The absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency related to the plasma
cell proliferative process. A skeletal survey is adequate to assess the presence of bone lesions if MGUS is
suspected. However, if other imaging studies (such as an MRI, CT, or PET/CT) are done, they should
demonstrate no evidence of bone lesions that can be attributed to the plasma cell disorder.

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 persons likely reflect renal dysfunction or polyclonal activation. (See
"Laboratory methods for analyzing monoclonal proteins", section on 'Use in patients with renal
insufficiency'.)

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
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 patients 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 patient with a non-IgM serum monoclonal protein ≥3 g/dL or with ≥10 percent clonal
plasma cells in the bone marrow does not have MGUS. In such a case, a diagnosis of MM or smoldering
MM (SMM) should be made based on the presence or absence of symptoms. 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 [64]. However, due to patchy
bone marrow involvement, approximately 4 percent of patients with MM will have a bone marrow
aspirate and biopsy demonstrating less than 10 percent clonal plasma cells [65].

While the diagnosis of MGUS requires the absence of anemia, hypercalcemia, renal failure, 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, patients with
MGUS may have anemia related to nutritional deficiency; renal failure related to coexisting diabetes or
hypertension; hypercalcemia due to hyperparathyroidism; or lytic bone lesions from metastatic
carcinoma. Only patients 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 "Clinical features, laboratory
manifestations, and diagnosis of multiple myeloma".)

●The presence of osteolytic lesions and unexplained hypercalcemia strongly suggests MM, but metastatic
carcinoma must be excluded.

●MRI of the skull, spine, and pelvis may be of value in distinguishing between MGUS and overt MM in
patients with symptomatic bone disease and a normal radiographic bone survey. In one series, MRI was
normal in patients with MGUS and abnormal in more than 80 percent of those with overt MM [66].

●Similarly, unexplained renal insufficiency suggests possible involvement by the light chains due to
MGUS, MM or a related malignancy. If renal dysfunction is not accompanied by significant light chain
excretion or other features of MM, a renal biopsy may be needed to ascertain that the renal failure is
caused by the plasma cell proliferative process [67]. (See "Indications for and complications of renal
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 [47,48,68-72]. However, a
clearly elevated level of beta-2 microglobulin in the absence of renal failure and/or an inflammatory
process would suggest a diagnosis of MM, and the patient 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
"Overview of the management of multiple myeloma".)

Smoldering multiple myeloma — Smoldering multiple myeloma (SMM), also called asymptomatic MM,
is an intermediate stage between MGUS and symptomatic MM. SMM is diagnosed in persons who meet
the following criteria (table 4) [61,73,74]:

●Serum monoclonal protein ≥3 g/dL and/or ≥10 to <60 percent bone marrow clonal plasma cells

●Absence of lytic lesions, anemia, hypercalcemia, and renal insufficiency (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 "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma",
section on 'Smoldering multiple myeloma'.)

SMM is distinguished from MM based on the absence or presence of end-organ damage (hypercalcemia,
anemia, bone lesions, renal failure) that is thought to be related to the underlying plasma cell disorder.
Patients with SMM should have less than 60 percent bone marrow clonal plasma cells. Patients 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) [75]. Therefore, such patients are best
considered as having MM even in the absence of end-organ damage. Similarly, patients with serum
involved/uninvolved free light chain (FLC) ratio of 100 or more, and those with >1 focal lesion on MRI
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) [76]. FLCs are present in a subset of patients
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, renal failure or other myeloma-defining events, WM, or
AL amyloidosis

Secondary MGUS — Secondary MGUS refers to the development of a new monoclonal protein during
the course of MM that has an isotype (heavy and/or light chain) distinct from the original clone (eg, IgM
MGUS in a patient 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 [77]. More than one isotype
occurred in approximately 30 percent of patients. Secondary MGUS was more common among patients
who had undergone hematopoietic cell transplantation and was associated with superior survival. The
MGUS 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 patients 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 [78].
Abnormalities in MYD88 can be seen in both WM and IgM MGUS [79,80]. 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 [81]:

●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

Patients without end-organ damage such as anemia, constitutional symptoms, hyperviscosity,

lymphadenopathy, or hepatosplenomegaly related to the plasma cell proliferative process must be
followed closely [63]. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of
Waldenström macroglobulinemia", section on 'Clinical presentation'.)

AL amyloidosis — Primary (amyloid light chain) amyloidosis and light chain deposition disease are
plasma 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. These fibrils can produce the nephrotic syndrome, heart failure,
hepatomegaly, 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. (See "Pathogenesis of immunoglobulin light chain (AL) amyloidosis and light and
heavy chain deposition diseases" 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, renal failure, and
lytic bone lesions related to the plasma cell proliferative disorder. However, the presence of renal failure
in conjunction with an M-protein does not automatically indicate AL amyloidosis, since these
abnormalities may be totally unrelated (eg, MGUS in a patient with renal failure secondary to diabetic or
hypertensive nephropathy).

The diagnosis of primary (AL) amyloidosis is initially suspected from typical clinical findings (eg,
macroglossia, nephrotic range proteinuria, restrictive cardiomyopathy, in conjunction with a serum or
urinary monoclonal 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

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. Patients 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: Plasma cell
dyscrasias".)

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

●Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant

clonal plasma cell or lymphoplasmacytic proliferative disorder (table 5). MGUS occurs in over 3 percent
of the general Caucasian population over the age of 50 and is typically detected as an incidental finding
when patients undergo a protein electrophoresis as part of an evaluation for a wide variety of clinical
symptoms and disorders.

●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 patients 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 Waldenström macroglobulinemia
and then symptomatic Waldenström macroglobulinemia, lymphoma, or AL amyloidosis. Infrequently,
IgM MGUS can progress to IgM multiple myeloma.

•Light chain MGUS (LC-MGUS) may progress to idiopathic Bence Jones proteinuria and to light chain
multiple myeloma, AL amyloidosis, or light chain deposition disease.

●The presence of MGUS is suspected in an asymptomatic patient in whom a serum monoclonal

immunoglobulin has been detected in a concentration of <3 g/dL. (See 'Epidemiology' above.)

●At a minimum, patients suspected of having MGUS should be evaluated with the following studies
(algorithm 1) (see 'Evaluation' above):

•Complete blood count

•Serum calcium and creatinine

•Serum protein electrophoresis and immunofixation

•Urine protein electrophoresis and immunofixation – The serum free light chain (FLC) assay can be used
initially in place of urine studies. However, if a monoclonal protein is seen on serum studies or if the
serum FLC ratio is abnormal, urine electrophoresis and immunofixation need to be performed.

•Serum FLC assay

•Quantitation of immunoglobulins

•Imaging – A metastatic bone survey is necessary for most patients with MGUS. This skeletal survey may
be omitted in patients with low-risk MGUS (ie, IgG-type MGUS with serum M-protein <1.5 g/dL and a
normal serum FLC ratio) and in patients with IgM MGUS with no clinical concern for bone lesions or
myeloma. Cross sectional imaging is preferred if there is clinical concern for multiple myeloma. (See
"Clinical features, laboratory manifestations, and diagnosis of multiple myeloma", section on 'Imaging'.)

●The diagnosis of MGUS (non-IgM and IgM) is confirmed when the following criteria have been met
(table 4) (see 'Diagnostic criteria' above):

•The presence of a serum monoclonal protein (M-protein, whether IgA, IgG, or IgM), at a concentration
<3 g/dL.

•Fewer than 10 percent plasma cells in the bone marrow. A bone marrow evaluation may be deferred in
patients with low-risk MGUS (IgG-type MGUS with serum M-protein <1.5 g/dL, a normal serum FLC
ratio), and with no bone pain or clinical concern for myeloma. A 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; and in patients with IgM MGUS
with a small M-protein (<1.5 g/dL), normal serum FLC ratio, with no evidence of anemia,
lymphadenopathy, or organomegaly.

•The absence of lytic bone lesions, anemia, hypercalcemia, and renal insufficiency or other myeloma-
defining events related to the plasma cell proliferative process.

•Patients 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.

●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). (See 'Differential diagnosis' above.)

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