Back To Search Results

Monoclonal Gammopathy of Undetermined Significance

Editor: Hani M. Babiker Updated: 7/10/2022 12:25:51 PM

Introduction

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 3 g/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:[1]

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

Etiology

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Etiology

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 and HIV liver disease.[2][4][5] 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.[6][7]

Epidemiology

Monoclonal gammopathy of undetermined significance (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.[2][4]

Pathophysiology

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][5]

History and Physical

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 (3 g/dL)
  2. Less than 10% of clonal plasma cells in the bone marrow
  3. The absence of CRAB symptoms (hypercalcemia, renal insufficiency, anemia and, bone lesions 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).[8][1][5]

Evaluation

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, quantification of immunoglobulins, immunophenotyping utilizing flow cytometry and cross-sectional imaging studies.[8][1]

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 serum and urine protein electrophoresis, and 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.[9][1]

The 2019 International myeloma working group (IMWG), consensus recommends the following approach for cross-sectional imaging in MGUS:[10]

Whole-body imaging is recommended only in high-risk MGUS. Since IgM-MGUS usually progresses to Waldenstrom 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.

Treatment / Management

Treatment is usually not recommended for patients with MGUS. As there is a risk of progression to lymphoproliferative malignancy long-term follow-up is advised.

If a patient has an IgM M-protein, bone marrow biopsy and computed tomography (CT) scanning of the abdomen may be helpful in detecting Waldenström macroglobulinemia or other lymphoproliferative disorders.

MGUS-associated neuropathies are usually not treated, except in the case of a disabling IgM monoclonal gammopathy or IgG/IgA MGUS associated with chronic inflammatory demyelinating neuropathy (CIDP). About 80% of patients with IgG/IgA MGUS CIDP respond to one of the typical CIDP treatments and some patients stabilize without therapy. MGUS patients with associated osteopenia or osteoporosis may benefit from treatment with intravenous bisphosphonates.

The intensity of follow-up in patients with MGUS is guided by risk stratification. Initial follow-up at six months is recommended, with subsequent visits scheduled according to the level of risk. If clinical trials of preventive strategies are available, patients at high risk for progression should be encouraged to participate.

Differential Diagnosis

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:

  • Plasma cell myeloma (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 providers 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.[5]
  • 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:[5]
    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.[11]
  • 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

Prognosis

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 an 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 providers believe that all non-IgM MGUS patients should undergo a clinical examination and laboratory evaluation for disease progression annually.[8] The patients with MGUS who are at risk for progressing to advanced disease can be risk-stratified based on the following criteria:

  1. Serum monoclonal protein level greater than or equal to 15 g/L (1.5 g/dL)
  2. Non-IgG MGUS (i.e., IgA, IgM, and IgD MGUS)
  3. Abnormal serum free light chain ratio

Patients with three risk factors are categorized as high-risk MGUS; patients with two 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.[9][5][12][13][14]

Complications

Monoclonal gammopathy of undetermined significance (MGUS) can progress to develop myeloproliferative disorders or other serious conditions such as:

  • Multiple myeloma
  • Light chain amyloidosis
  • Waldenstrom macroglobulinemia
  • Lymphoma
  • Osteoporosis
  • Venous thromboembolism

Deterrence and Patient Education

Monoclonal gammopathy of undetermined significance (MGUS) patients have no specific treatment, they should undergo detail clinical examination, serum, and urine protein electrophoresis regularly every six to twelve months to look for disease progression. Patients with osteopenia or osteoporosis may benefit from bisphosphonate therapy.

Enhancing Healthcare Team Outcomes

Monoclonal gammopathy of undetermined significance (MGUS) is best managed by an interprofessional team that includes primary care providers, hematologists, medical oncologists, and nurses. There is no specific treatment for these patients, they only need long-term follow-up because of the potential to progress to myeloproliferative disorders and numerous other complications.

References


[1]

Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. The Lancet. Oncology. 2014 Nov:15(12):e538-48. doi: 10.1016/S1470-2045(14)70442-5. Epub 2014 Oct 26     [PubMed PMID: 25439696]


[2]

Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance. British journal of haematology. 2006 Sep:134(6):573-89     [PubMed PMID: 16938117]


[3]

Dispenzieri A, Katzmann JA, Kyle RA, Larson DR, Melton LJ 3rd, Colby CL, Therneau TM, Clark R, Kumar SK, Bradwell A, Fonseca R, Jelinek DF, Rajkumar SV. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet (London, England). 2010 May 15:375(9727):1721-8. doi: 10.1016/S0140-6736(10)60482-5. Epub     [PubMed PMID: 20472173]

Level 2 (mid-level) evidence

[4]

Weinhold N, Johnson DC, Rawstron AC, Försti A, Doughty C, Vijayakrishnan J, Broderick P, Dahir NB, Begum DB, Hosking FJ, Yong K, Walker BA, Hoffmann P, Mühleisen TW, Langer C, Dörner E, Jöckel KH, Eisele L, Nöthen MM, Hose D, Davies FE, Goldschmidt H, Morgan GJ, Hemminki K, Houlston RS. Inherited genetic susceptibility to monoclonal gammopathy of unknown significance. Blood. 2014 Apr 17:123(16):2513-7; quiz 2593. doi: 10.1182/blood-2013-10-532283. Epub 2014 Jan 21     [PubMed PMID: 24449210]


[5]

Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016 May 19:127(20):2375-90. doi: 10.1182/blood-2016-01-643569. Epub 2016 Mar 15     [PubMed PMID: 26980727]


[6]

Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Mellqvist UH, Wahlin A, Bjorkholm M, Turesson I. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood. 2009 Jul 23:114(4):791-5. doi: 10.1182/blood-2008-12-191676. Epub 2009 Jan 30     [PubMed PMID: 19182202]

Level 2 (mid-level) evidence

[7]

Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL, Phelps TK, Dispenzieri A, Kumar SK, Katzmann JA, Rajkumar SV. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood. 2009 Jul 23:114(4):785-90. doi: 10.1182/blood-2008-12-192575. Epub 2009 Jan 29     [PubMed PMID: 19179466]


[8]

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. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014 Jan 2:123(1):78-85. doi: 10.1182/blood-2013-07-515239. Epub 2013 Oct 21     [PubMed PMID: 24144643]

Level 2 (mid-level) evidence

[9]

Kyle RA, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Cerhan JR, Rajkumar SV. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. The New England journal of medicine. 2018 Jan 18:378(3):241-249. doi: 10.1056/NEJMoa1709974. Epub     [PubMed PMID: 29342381]


[10]

Hillengass J, Usmani S, Rajkumar SV, Durie BGM, Mateos MV, Lonial S, Joao C, Anderson KC, García-Sanz R, Riva E, Du J, van de Donk N, Berdeja JG, Terpos E, Zamagni E, Kyle RA, San Miguel J, Goldschmidt H, Giralt S, Kumar S, Raje N, Ludwig H, Ocio E, Schots R, Einsele H, Schjesvold F, Chen WM, Abildgaard N, Lipe BC, Dytfeld D, Wirk BM, Drake M, Cavo M, Lahuerta JJ, Lentzsch S. International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders. The Lancet. Oncology. 2019 Jun:20(6):e302-e312. doi: 10.1016/S1470-2045(19)30309-2. Epub     [PubMed PMID: 31162104]

Level 3 (low-level) evidence

[11]

Leung N, Bridoux F, Hutchison CA, Nasr SH, Cockwell P, Fermand JP, Dispenzieri A, Song KW, Kyle RA, International Kidney and Monoclonal Gammopathy Research Group. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012 Nov 22:120(22):4292-5. doi: 10.1182/blood-2012-07-445304. Epub 2012 Oct 9     [PubMed PMID: 23047823]


[12]

Baldini L, Guffanti A, Cesana BM, Colombi M, Chiorboli O, Damilano I, Maiolo AT. Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood. 1996 Feb 1:87(3):912-8     [PubMed PMID: 8562962]


[13]

Rosiñol L, Cibeira MT, Montoto S, Rozman M, Esteve J, Filella X, Bladé J. Monoclonal gammopathy of undetermined significance: predictors of malignant transformation and recognition of an evolving type characterized by a progressive increase in M protein size. Mayo Clinic proceedings. 2007 Apr:82(4):428-34     [PubMed PMID: 17418070]


[14]

Cesana C, Klersy C, Barbarano L, Nosari AM, Crugnola M, Pungolino E, Gargantini L, Granata S, Valentini M, Morra E. Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2002 Mar 15:20(6):1625-34     [PubMed PMID: 11896113]


[15]

Zeig-Owens R, Goldfarb DG, Luft BJ, Yang X, Murata K, Ramanathan L, Thoren K, Doddi S, Shah UA, Mueller AK, Hall CB, Giricz O, Verma A, Prezant DJ, Landgren O. Myeloma precursor disease (MGUS) among rescue and recovery workers exposed to the World Trade Center disaster. Blood cancer journal. 2022 Aug 22:12(8):120. doi: 10.1038/s41408-022-00709-2. Epub 2022 Aug 22     [PubMed PMID: 35995768]


[16]

Kleinstern G, Larson DR, Allmer C, Norman AD, Muntifering G, Sinnwell J, Visram A, Rajkumar V, Dispenzieri A, Kyle RA, Slager SL, Kumar S, Vachon CM. Body mass index associated with monoclonal gammopathy of undetermined significance (MGUS) progression in Olmsted County, Minnesota. Blood cancer journal. 2022 Apr 19:12(4):67. doi: 10.1038/s41408-022-00659-9. Epub 2022 Apr 19     [PubMed PMID: 35440099]


[17]

Tahiru W, Izarra Santamaria A, Hultdin J, Wu WY, Späth F. Progression patterns in monoclonal gammopathy of undetermined significance and multiple myeloma outcome: a cohort study in 42 patients. Experimental hematology & oncology. 2022 Feb 23:11(1):8. doi: 10.1186/s40164-022-00259-0. Epub 2022 Feb 23     [PubMed PMID: 35197127]


[18]

McCall B, Ibrahim Z, Barth P, Aaron RK. Monoclonal Gammopathies in a Fracture Liaison Service. Rhode Island medical journal (2013). 2022 Oct 3:105(8):28-32     [PubMed PMID: 36173906]


[19]

Mouhieddine TH, Weeks LD, Ghobrial IM. Monoclonal gammopathy of undetermined significance. Blood. 2019 Jun 6:133(23):2484-2494. doi: 10.1182/blood.2019846782. Epub 2019 Apr 22     [PubMed PMID: 31010848]