Monoclonal gammopathy of undetermined significance (MGUS) is usually asymptomatic and is often detected incidentally during routine laboratory tests. It is a plasma cell lymphoproliferative disorder with the potential of progressing to a malignancy or multiple myelomas (MM) [1]. It commonly occurs in individuals above the age of 50 and a higher incidence has been reported amongst Africans from America as well as from Africa [2] [3]. Other risk factors of MGUS include older age [1], family history, male sex [4], immunosuppression, and a history of pesticide exposure [5].

Although MGUS itself is asymptomatic, patients typically have clinical symptoms and signs of other disorders like osteoporosis, venous thrombosis [6], peripheral neuropathy, vasculitis, hemolytic anemia, skin rashes, gout or hypercalcemia.

Rajkumar et al [7] have described three clinical types MGUS with their own individual stages of progressing from a premalignant stage to an intermediate stage to a malignant stage. These are:

• Non-immunoglobulin (Ig)M MGUS (IgG, IgA, or IgD MGUS): This is the commonest subtype of MGUS. It can progress to either an asymptomatic form of MM or to symptomatic MM. Rarely, it can progress to AL amyloidosis, or light chain deposit disease, or another lymphoproliferative disorder.
• IgM MGUS: IgM MGUS can progress to either asymptomatic Waldenström macroglobulinemia or to symptomatic Waldenström macroglobulinemia and rarely to lymphoma or AL amyloidosis or IgM MM [8] [9].
• Light chain MGUS: this is a precursor to a light chain MM and almost 20% of new MM cases are of this type [10]. Idiopathic Bence Jones proteinuria represents the equivalent of symptomatic MM or asymptomatic Waldenström macroglobulinemia with light chain monoclonal gammopathies.

• Asymptomatic

  Monoclonal gammopathy of undetermined significance (MGUS) is usually asymptomatic and is often detected incidentally during routine laboratory tests. [symptoma.com]

  It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. [ncbi.nlm.nih.gov]

  Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic disorder associated with an increased risk of developing multiple myeloma and related plasma cell proliferative malignancies. [bestpractice.bmj.com]

• Lymphedema

  Our aim was to investigate whether a monoclonal gammopathy could be a causal factor in progressive lymphedema. [ncbi.nlm.nih.gov]

• Myopathy

  PURPOSE OF REVIEW: Sporadic late-onset nemaline myopathy (SLONM) with monoclonal gammopathy of undetermined significance (MGUS) is a rare subacute progressive muscle disease. The prognosis is poor due to severe respiratory insufficiency. [ncbi.nlm.nih.gov]

• Corneal Deposit

  Corneal deposits may be the only manifestation of monoclonal gammopathy of undetermined significance in patients who are otherwise systemically asymptomatic. [ncbi.nlm.nih.gov]

• Corneal Edema

  During post-surgical follow-up, corneal edema and stromal opacity recurred, and penetrating keratoplasty was performed two more times. [ncbi.nlm.nih.gov]

MGUS is usually diagnosed incidentally when patients are being evaluated with serum protein electrophoresis for clinical features of osteoporosis, or hypercalcemia or elevated erythrocyte sedimentation rate, venous thrombosis, etc. MGUS can be easily evaluated and monitored with blood tests and therefore its conversion to a malignancy can be easily observed [11]. A thorough workup for MGUS includes a complete blood count to detect anemia, thrombocytopenia, and leukopenia; renal function tests, serum uric acid levels, and lactate dehydrogenase levels [12]. The gold standard test for diagnosis of MGUS is serum and urine electrophoresis. Tests to determine prognosis include beta2 microglobulin, C-reactive protein, and serum free light chain assay. The progression of MGUS can be evaluated with quantitative immunoglobulin measurements.

Lytic bone lesions are usually noticed on a radiological skeletal survey and it should be performed for documentation as it can predict sites of pathological fractures. Bone marrow biopsy helps to detect abnormal cytogenetics [13] and is indicated in patients with IgA and IgM M-proteins but is not recommended in patients with IgG MGUS unless their serum M-protein level is > 1.5 g/dL or there is evidence of end-organ damage [14].

Indeed, multiple myeloma has perhaps seen more remarkable progress in treatment and patient outcomes than any other cancer during the last decade. [ncbi.nlm.nih.gov]

The treatment of MGRS-related kidney diseases should be tailored to the clone responsible. In the past, part of the reticence for withholding treatment was that alkylators were the only antiplasma cell therapies available. [doi.org]

Conclusions : Exudative maculopathy unresponsive to conventional treatment may suggest an underlying hematologic condition. [iovs.arvojournals.org]

KEYWORDS: DNA copy-number changes; DNA microarrays; monoclonal gammopathies; prognosis [ncbi.nlm.nih.gov]

In the future, continued improvement in our understanding of MGUS will lead to the development of better biomarkers for prognosis and therapies for chemoprevention of MM. [doi.org]

The etiology of the prothrombotic state in myeloma has yet to be definitively characterized. [ncbi.nlm.nih.gov]

Author information 1 Myeloma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. 2 Divsion of Cancer Epidemiology and Genetics, Biostatistics Branch, National Cancer Institute, Rockville, MD, USA. 3 Division of [ncbi.nlm.nih.gov]

In a real life exhaustive study, the Martinique Cancer Registry proposes an epidemiological focus on MGUS in Martinique. [mona.uwi.edu]

The medical-records-linkage system of the Rochester Epidemiology Project 12 makes possible complete case ascertainment among Olmsted County residents. [doi.org]

Thus we propose a possible pathophysiologic link between the gammopathy-associated factors and the generation of lymphedema with initial fibrogenesis aggravating pre-existing lipedema. [ncbi.nlm.nih.gov]

“Monoclonal gammopathy of undetermined significance and smoldering myeloma: new insights into pathophysiology and epidemiology”. Hematology Am Soc Hematol Educ Program.. vol. 2010. 2010. pp. 295-302. [cancertherapyadvisor.com]

More prevalent in African Americans than Caucasians (2 - 3 fold) ( Leukemia 2014;28:1537 ) More common in men than women (1.5:1) Non-IgM MGUS represents up to 85% of MGUS cases Pathophysiology Origin is clonal mature plasma cells residing in the bone [pathologyoutlines.com]

Etiologic Factors for MGUS and Prospects for Primary Prevention Recent observations offer important clues, indicating that genetic predisposition and potentially preventable environmental factors may play a key role in the development of MGUS. [doi.org]

This progression cannot be prevented. [merckmanuals.com]

1. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis of monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564-569
2. Landgren O, Gridley G, Turesson I, et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood. 2006;107(3):904-906
3. Landgren O, Katzmann JA, Hsing AW, et al. Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. Mayo Clin Proc. 2007;82(12):1468-1473
4. Vachon CM, Kyle RA, Therneau TM, et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood. 2009;114(4):785-790
5. Landgren O, Kyle RA, Hoppin JA, et al. Pesticide exposure and risk of monoclonal gammopathy of undetermined significance (MGUS) in the Agricultural Health Study. Blood. 2009;113(25):6386-6391
6. Bida JP, Kyle RA, Therneau TM, et al. Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients. Mayo Clin Proc. 2009;84(8):685-693
7. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538
8. Kyle RA, Therneau TM, Rajkumar SV, et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood. 2003;102:3759-3764
9. Schuster S, Rajkumar SV, Dispenzieri A, et al. IgM multiple myeloma: disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia. Am J Hematol. 2010 Nov; 85 (11): 853 -855
10. Dispenzieri A, Katzmann JA, Kyle RA, et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet. 2010;375:1721-1728
11. Rajkumar SV. Prevention of progression in monoclonal gammopathy of undetermined significance. Clin Cancer Res. 2009;15(18):5606-5608
12. Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009 Aug; 55(8):1517-22.
13. Greenberg AJ, Cousin M, Kumar S, et al. Differences in the distribution of cytogenetic subtypes between multiple myeloma patients with and without a family history of monoclonal gammopathy and multiple myeloma. Eur J Haematol. 2013 Sep; 91 (3 ): 193 -195
14. [Guideline] van de Donk NW, Palumbo A, Johnsen HE, et al. The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network. Haematologica. 2014 Jun; 99 (6):984-96.