Monoclonal Gammopathy Of Undetermined Significance (MGUS)

Article Author:
Hatem Kaseb
Article Editor:
Hani Babiker
1/15/2020 3:23:08 PM
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Monoclonal Gammopathy Of Undetermined Significance (MGUS)


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, 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 [1]There are 2 distinct types of MGUS [2]

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

Non-IgM MGUS may progress to a malignant plasma cell neoplasm. IgM MGUS is considered a separate entity by the 2017 WHO classification. IgM MGUS may progress to Waldenstrom macroglobulinemia, immunoglobulin light chain (AL) amyloidosis, or lymphoma. Light chain 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 [3]


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 [3][4][2]


MGUS is found in approximately 2% to 3% of adults over age 50 and in approximately 5% of adults older than the age of 70. MGUS is more common in men than in women (- 1.5:1) and 2-fold to 3-fold more common in African Americans compared to Caucasians. Non-IgM MGUS represents up to 85% of MGUS cases; IgM MGUS represents up to 15% of MGUS cases [3][4]


The clonal plasma cells producing non-IgM MGUS reside in the bone marrow (BM). These cells harbor somatic hypermutation of the variable regions and are class-switched. The majority of non-IgM MGUS are IgG, followed by IgA, bi-clonal, and IgD [1][2]

History and Physical

The majority of non-IgM MGUS patients are asymptomatic. According to the WHO 2017, Non-IgM MGUS diagnosis is based on 3 diagnostic criteria:

  1. Serum monoclonal protein less than 30 g/L 
  2. Less than 10% clonal plasma cells in the BM 
  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 show progression 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) [5][1][2]


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 serum free light chains (FLC) assay, quantitation of immunoglobulins, bone survey of skull, spine, and pelvis (plain x-ray, computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET)), immunophenotyping utilizing flowcytometry, and/or genetic testing.[5][1][5]

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 [6][1]

Differential Diagnosis

It is important to distinguish non-IgM MGUS from other advanced plasma cell neoplasms since these diseases will require a different management approach. The differential diagnosis of non-IgM MGUS include:

  • 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 [2]
  • 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 and/or splenomegaly. The WHO (2017) diagnostic criteria of WM include[2]:
  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 [7]
  • 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


Non-IgM MGUS is considered a preneoplastic condition with an annual risk of progression of approximately 1%. Risk of progression is increased when M protein greater than or equal to 15 g/L and with abnormal free light chain ratio. Non-IgM MGUS does not require treatment. However, the management of patients with non-IgM MGUS requires an understanding of the risk of progression of the disease. Generally, close follow-up is recommended for these patients. Most physicians believe that all non-IgM MGUS patients should undergo clinical examination and laboratory evaluation for disease progression annually [5]Some physicians prefer to risk stratify patients based on the following criteria:

  1. Serum monoclonal protein level greater than or equal to 15 g/L
  2. Non-IgG MGUS (i.e., IgA, IgM, and IgD MGUS)
  3. Abnormal serum free light chain ratio

Patients with 3 risk factors are categorized as high-risk MGUS; patients with 2 risk factors are categorized as high-intermediate risk MGUS. Patients with one risk factor are categorized as low-intermediate risk MGUS. Patients with no risk factors are categorized as low-risk MGUS. Despite close observation, some non-IgM MGUS patients may show progression to PCM abruptly [6][2]

Enhancing Healthcare Team Outcomes

MGUS is best managed by an interprofessional team that includes nurses. These patients need long term follow up because of the potential to numerous complications.


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[5] Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120)., Dhodapkar MV,Sexton R,Waheed S,Usmani S,Papanikolaou X,Nair B,Petty N,Shaughnessy JD Jr,Hoering A,Crowley J,Orlowski RZ,Barlogie B,, Blood, 2014 Jan 2     [PubMed PMID: 24144643]
[6] Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance., Kyle RA,Larson DR,Therneau TM,Dispenzieri A,Kumar S,Cerhan JR,Rajkumar SV,, The New England journal of medicine, 2018 Jan 18     [PubMed PMID: 29342381]
[7] Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant., Leung N,Bridoux F,Hutchison CA,Nasr SH,Cockwell P,Fermand JP,Dispenzieri A,Song KW,Kyle RA,, Blood, 2012 Nov 22     [PubMed PMID: 23047823]