Monoclonal Gammopathy of Undetermined Significance (MGUS)

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Monoclonal Gammopathy of Undetermined Significance (MGUS) is characterized by a serum M protein concentration of less than 30 g/L, fewer than 10% clonal plasma cells in the bone marrow, and the absence of end-organ damage that can be attributed to the plasma cell proliferative disorder. End-organ damage is defined by hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) related to the plasma cell proliferative disease.

Monoclonal gammopathies are disorders characterized by a homogeneous immunoglobulin (the M-protein) spike in serum or urine arising from the proliferation of an abnormal clone of a single plasma cell precursor. Multiple myeloma (MM) is the archetype of a malignant monoclonal plasma cell disorder. Benign monoclonal gammopathies, as first described by Waldenström, also occur and are much more common than MM. Once it was observed that a substantial proportion of benign gammopathies develop into MM, the now universally accepted term monoclonal gammopathy of undetermined significance (MGUS) was introduced to describe the disorder.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder that is characterized by the presence of serum M-protein less than 30 g/L or 3g/dL, bone marrow (BM) clonal plasma cells less than 10%, absence of plasma cell myeloma (PCM) related end-organ damage (CRAB symptoms: hypercalcemia, renal insufficiency, anemia and, bone lesions) and absence of B-cell lymphoma or other disease known to produce an M-protein. MGUS is generally considered a preneoplastic disorder that does not always progress to overt malignancy.

Types of Monoclonal Gammopathy of Undetermined Significance (MGUS)

There are three distinct types of MGUS 

  1. Non-IgM MGUS
  2. IgM MGUS: Non-IgM MGUS (IgG, IgA, IgD) accounts for the majority of MGUS cases and is characterized by a monoclonal plasma cell.
  3. Light-chain MGUS

Non-IgM MGUS may progress to a malignant plasma cell neoplasm.  IgM MGUS may develop into Waldenstrom macroglobulinemia, immunoglobulin light chain (AL) amyloidosis, or lymphoma. Light chain MGUS (LC-MGUS) is characterized by a monoclonal protein that lacks the immunoglobulin heavy chain component. LC-MGUS may show progression to idiopathic Bence Jones proteinuria, light chain PCM, AL amyloidosis, or light chain deposition disease. According to a population-based cohort study, the risk of progression to multiple myeloma in patients with light-chain MGUS is 0.3%

Causes of Monoclonal Gammopathy of Undetermined Significance (MGUS)

No specific cause of Non-IgM MGUS has been identified. However, the disease may be associated with some non-malignant disorders such as connective tissue disorders, peripheral neuropathies, dermatological diseases such as acquired C1 esterase inhibitor deficiency (angioedema), endocrine diseases, and liver infections such as hepatitis C virus infection liver and HIV liver disease . Population-based studies from northern Europe and the United States show increased risk of MGUS among first-degree relatives of those with MGUS or Myeloma, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.

Risk factors for progression

It is not possible to predict which patients with MGUS will remain stable and which will experience progression at a subsequent time.[] However, a number of parameters are helpful in predicting the likelihood of progression of MGUS to MM.

Size of the M protein

The size of the M protein at the time of recognition of MGUS is the most important predictor of progression.[] Twenty years after the recognition of MGUS, the risk of progression to MM or a related disorder was 14% for patients with an initial M protein value of ≤ 0.5 g/dL, 25% for those in whom the value was 1.5 g/dL, 41% for those in whom the value was 2.0 g/dL, and 49% in those with an M spike of 2.5 g/dL. The risk of progression in a patient with an M protein of 1.5 g/dL was almost double that of a patient with an M protein of 0.5 g/dL. The risk of progression with an M protein of 2.5 g/dL was 4.6 times that of a patient with an M protein of 0.5 g/dL. Also, a progressive increase in the size of the M protein during the first year of follow-up is an important risk factor for progression.[]

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Type of serum M protein

In our series of 1,384 patients, those who had an IgM or an IgA monoclonal protein had an increased risk of progression compared with patients who had an IgG protein.[]

Bone marrow plasma cells

The presence of more than 5% bone marrow plasma cells was an independent risk factor for progression in one series.[ ] Baldini et al[] recognized a malignant transformation rate of 6.8% during follow-up when the bone marrow plasma cell was less than 10%; however, the rate was 37% for those with bone marrow plasmacytosis of 10% to 30%.

Serum FLC ratio

In a study of 1,148 of the 1,384 MGUS patients from southeastern Minnesota, we found an abnormal FLC ratio in 33%. Progression occurred in 7.6% of these patients at 15 years of follow-up. The risk of progression in patients with an abnormal FLC ratio was higher than in patients with a normal ratio (HR, 3.5) and was independent of the concentration and type of serum M protein.[]

Symptoms of Monoclonal Gammopathy of Undetermined Significance (MGUS)

People with monoclonal gammopathy generally do not experience signs or symptoms.[rx] Some people may experience a rash or nerve problems, such as numbness or tingling.[rx] Severe renal disease has also been found in a subset of those with monoclonal gammopathy.[rx] MGUS is usually detected by chance when the patient has a blood test for another condition or as part of standard screening.[rx]

Most people who have abnormal proteins in their blood will never get worse. But in some cases, these illnesses can develop:

  • Multiple myeloma
  • Non-Hodgkin lymphoma
  • Plasma cell leukemia
  • Primary amyloidosis
  • Solitary plasmacytoma
  • Waldenstrom’s macroglobulinemia

Diagnosis of Monoclonal Gammopathy of Undetermined Significance (MGUS)

The majority of non-IgM MGUS patients are asymptomatic. According to the 2014 International Myeloma Working Group updated criteria, the diagnosis of Non-IgM MGUS is based on three criteria:

  1. Serum monoclonal protein less than 30 g/L (3g/dL)
  2. Less than 10% clonal plasma cells in the bone marrow
  3. The absence of CRAB symptoms suspicious for PCM

Non-IgM MGUS is usually diagnosed as an incidental finding on protein electrophoresis performed as part of an evaluation for disorders or disease presentation of peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, hypercalcemia, elevated erythrocyte sedimentation rate. Non-IgM MGUS is generally not considered a neoplastic process, with an annual risk of progression of 1%. Non-IgM MGUS may progress to PCM, solitary plasmacytoma, or amyloidosis. Two important factors influence non-IgM MGUS progression. The first is the size and type of M protein, and the second is the level of immunoglobulin (less than 5 g/L and greater than 25 g/L) 


Non-IgM MGUS needs a thorough set of investigations to exclude this disease entity from the other plasma cell neoplasms. Investigations should include complete blood count (CBC), bone marrow aspirate/biopsy (BMA/BMB), immunohistochemical analysis (IHC), serum calcium and creatinine, serum protein electrophoresis and immunofixation, urine protein electrophoresis and immunofixation,serum-free light chains (FLC) assay, quantitation of immunoglobulins, immunophenotyping utilizing flow cytometry and cross-sectional imaging studies.

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CBC/peripheral smear is usually normal. However, some cases may show rouleaux formation. BMB usually shows 3% to 5% mature plasma cells (less than 10%) evenly scattered or in occasional small clusters. CD138 is useful in highlighting these plasma cells in the BMB. IHC of the plasma cells for kappa and lambda will demonstrate monoclonal restriction. MGUS is characterized by the presence of a monoclonal (M) protein which is produced by clonal plasma cells and detected by SPEP, UPEP and/or immunofixation of the serum and urine. Immunophenotyping shows monoclonal plasma cells that are CD38+ (bright) cells with an aberrant CD56 population (may also be negative). Molecular testing for Non-IgM MGUS has shown that this disease entity usually shows a normal karyotype because of the relatively small number of plasma cells. Some patients show chromosomal alterations of PCM that include: t(11;14), t(4;14), t(14;16), deletions of 13q and hyperdiploid. No clinical correlation for these genetic alterations has been found in non-IgM MGUS 

The 2019 International Myeloma Working Group (IMWG), consensus recommends the following approach for cross-sectional imaging in MGUS:

Whole-body imaging –  is recommended only in high-risk MGUS. Since IgM-MGUS usually progresses to Waldenstrom’s macroglobulinemia and not multiple myeloma routine, bone imaging is not recommended.

In suspected high-risk non-IgM MGUS –  a whole-body CT to rule out multiple myeloma is recommended. CT scan has superior sensitivity compared with a skeletal survey for the detection of osteolytic lesions in patients with multiple myeloma.

If whole-body CT – is not available, conventional skeletal survey or whole-body MRI are alternatives. In patients with equivocal findings on whole-body CT (or conventional skeletal survey) in whom there is a concern for myeloma development, a whole-body MRI is recommended(or MRI of the spine and pelvis if whole-body MRI is not available).

If whole-body CT is positive – a PET/CT should be done. A follow-up bone imaging is not recommended unless there are signs of progression to symptomatic disease (e.g., pain or increase in serological parameters). In patients with MGUS with positive imaging findings for focal and osteolytic lesions, other malignancies should be ruled out as well. If needed, a biopsy of such a lesion should be performed.

  • More-detailed blood tests – These can help rule out other causes of elevated protein levels and can check for kidney damage.
  • Urine tests – A 24-hour urine collection can help determine if abnormal protein is being released into your urine. It can also assess any resulting kidney damage.
  • Imaging tests – If you are experiencing bone pain, your doctor might recommend an MRI or ositron emission tomography (PET) scan. The images can help your doctor find bone abnormalities related to MGUS. Your bone density also might need to be checked.
  • Bone marrow test – A hollow needle can remove a portion of your bone marrow from the back of one of your hipbones. Bone marrow analysis is generally done only when you’re at risk of developing a more serious disease or if you have unexplained anemia, kidney failure, bone lesions or high calcium levels.

MGUS is a common, age-related medical condition characterized by an accumulation of bone marrow plasma cells derived from a single abnormal clone. Patients may be diagnosed with MGUS if they fulfill the following four criteria:[rx]

  1. A monoclonal paraprotein band less than 30 g/l (< 3g/dl);
  2. Plasma cells less than 10% on bone marrow examination;
  3. No evidence of bone lesions, anemia, hypercalcemia, or chronic kidney disease related to the paraprotein, and
  4. No evidence of another B-cell proliferative disorder.
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Differential diagnosis

Several other illnesses can present with a monoclonal gammopathy, and the monoclonal protein may be the first discovery before a formal diagnosis is made:

  • PCM (smoldering or symptomatic): Any patient with a non-IgM serum monoclonal protein greater than or equal to 30 g/L or with greater than or equal to 10% clonal plasma cells in the bone marrow should not be diagnosed as non-IgM MGUS. Many physicians consider smoldering PCM as a transition stage between non-IgM MGUS and symptomatic PCM. Smoldering PCM is distinguished from MGUS based on the size of the M protein and the percentage of clonal plasma cells in the bone marrow. Smoldering PCM is distinguished from symptomatic PCM by the presence of CRAB symptoms 
Waldenström macroglobulinemia (smoldering or symptomatic): WM is a distinct clinicopathologic disorder that shows lymphoplasmacytic lymphoma (LPL) in the bone marrow and an IgM monoclonal gammopathy. Symptoms include blood hyperviscosity, lymphadenopathy, or splenomegaly. The WHO (2017) diagnostic criteria of WM include:
  1. IgM monoclonal gammopathy
  2. Clonal plasma cells less than 10%
  3. Absence of end-organ damage (CRAB symptoms)
  4. Absence of symptoms or signs of amyloidosis
  • Monoclonal gammopathy of renal significance: This disease entity is diagnosed when the patient has diagnostic criteria for MGUS as well as renal insufficiency and monoclonal immunoglobulin deposits in the kidney by immunofluorescence 
Light chain smoldering multiple myeloma (idiopathic Bence Jones proteinuria): The diagnostic criteria of LC-SMM include:
  1. Monoclonal light chains in the urine (Bence Jones proteinuria)
  2. No immunoglobulin heavy chain expression in the serum or urine
  3. No symptoms of PCM, WM, or amyloid light chain amyloidosis
  • Primary (amyloid light chain) amyloidosis and light chain deposition disease: This entity of plasma cell neoplasms is associated with the pathologic deposition of monoclonal light chains in tissue. The diagnostic criteria include the presence of amyloid in tissue and evidence of plasma cell neoplasm.
  • B cell lymphoproliferative disorder
  • Multiple myeloma
  • Smouldering multiple myeloma
  • AIDS
  • Chronic lymphocytic leukemia
  • Non-Hodgkin lymphoma, particularly Splenic marginal zone lymphoma[rx] and Lymphoplasmocytic lymphoma
  • Hepatitis C
  • Connective tissue disease such as lupus[rx]
  • Immunosuppression following organ transplantation
  • Waldenström macroglobulinemia
  • Guillain–Barré syndrome[rx]
  • Tempi syndrome[rx]

Treatment of Monoclonal Gammopathy of Undetermined Significance (MGUS)

The protein electrophoresis test should be repeated annually, and if there is any concern for a rise in the level of monoclonal protein, then prompt referral to a hematologist is required. The hematologist, when first evaluating a case of MGUS, will usually perform a skeletal survey (X-rays of the proximal skeleton), check the blood for hypercalcemia and deterioration in renal function, check the urine for Bence Jones protein and perform a bone marrow biopsy. If none of these tests are abnormal, a patient with MGUS is followed up once every 6 months to a year with a blood test (serum protein electrophoresis). Although patients with MGUS have sometimes been reported to suffer from peripheral neuropathy, a debilitating condition which causes bizarre sensory problems to painful sensory problems,[rx] no treatment is indicated.



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