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. There are three distinct types of 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%
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.
MGUS is found in approximately 2% to 3% of adults over age 50 and in 5% of adults older than the age of 70. MGUS is more common in men than in women (1.5:1) and 2 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 
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:
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.
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.
It is crucial 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:
Non-IgM MGUS is considered a preneoplastic condition with an annual risk of progression of approximately 1%. The 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 a clinical examination and laboratory evaluation for disease progression annually . The patients with MGUS who are at risk for progressing to advanced disease can be risk-stratified based on the following criteria:
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 
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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