Monoclonal gammopathy of undetermined significance

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Monoclonal gammopathy of undetermined significance
Schematic representation of a normal protein electrophoresis gel. A small spike would be present in the gamma (γ) band in MGUS
Classification and external resources
ICD-10 D47.2
ICD-9-CM 273.1
ICD-O 9765/1
DiseasesDB 1341
eMedicine med/1495
MeSH D008998

Monoclonal gammopathy of undetermined significance (MGUS, unknown or uncertain may be substituted for undetermined), formerly benign monoclonal gammopathy, is a condition in which a paraprotein is found in the blood during standard laboratory blood tests. It resembles multiple myeloma and similar diseases, but the levels of antibody are lower, the number of plasma cells (white blood cells that secrete antibodies) in the bone marrow is lower, it has no symptoms or problems, and no treatment is indicated. However, multiple myeloma develops at the rate of about 1.5% a year, so doctors recommend monitoring it yearly. In rare cases, it may also be related with a slowly progressive symmetric distal sensorimotor neuropathy.[1]


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:[2]

  1. A monoclonal paraprotein band lesser 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 renal insufficiency related to the paraprotein, and
  4. No evidence of another B-cell proliferative disorder.

Differential diagnosis[edit]

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


Pathologically, the lesion in MGUS is in fact very similar to that in multiple myeloma. There is a predominance of clonal plasma cells in the bone marrow with an abnormal immunophenotype (CD38+ CD56+ CD19−) mixed in with cells of a normal phenotype (CD38+ CD56− CD19+);[7][8] in MGUS, on average more than 3% of the clonal plasma cells have the normal phenotype, whereas in multiple myeloma, less than 3% of the cells have the normal phenotype.[9] What causes MGUS to transform into multiple myeloma is as yet unknown.


At the Mayo Clinic, MGUS transformed into multiple myeloma or similar lymphoproliferative disorder at the rate of about 1-2% a year, or 17%, 34%, and 39% at 10, 20, and 25 years, respectively, of follow-up—among surviving patients. However, because they were elderly, most patients with MGUS died of something else and did not go on to develop multiple myeloma. When this was taken into account, only 11.2% developed lymphoproliferative disorders.[10]

Kyle studied the prevalence of myeloma in the population as a whole (not clinic patients) in Olmsted County, Minnesota. They found that the prevalence of MGUS was 3.2% in people above 50, with a slight male predominance (4.0% vs. 2.7%). Prevalence increased with age: of people over 70 up to 5.3% had MGUS, while in the over-85 age group the prevalence was 7.5%. In the majority of cases (63.5%), the paraprotein level was <1 g/dl, while only a very small group had levels over 2 g/dl.[11] A study of monoclonal protein levels conducted in Ghana showed a prevalence of MGUS of approximately 5.9% in African men over the age of 50.[12]

In 2009, prospective data demonstrated that all or almost all cases of multiple myeloma are preceded by MGUS.[13] In addition to multiple myeloma, MGUS may also progress to Waldenström's macroglobulinemia, primary amyloidosis, B-cell lymphoma, or chronic lymphocytic leukemia.


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).

See also[edit]


  1. ^ Kahn, S. N., Riches, P. G., & Kohn, J. (1980). Paraproteinaemia in neurological disease: incidence, associations, and classification of monoclonal immunoglobulins. Journal of clinical pathology, 33(7), 617-621. [1]
  2. ^ International Myeloma Working Group (2003). "Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group". Br J Haematol 121 (5): 749–757. doi:10.1046/j.1365-2141.2003.04355.x. PMID 12780789. 
  3. ^ Murakami H, Irisawa H, Saitoh T, Matsushima T, Tamura J, Sawamura M, Karasawa M, Hosomura Y, Kojima M (1997). "Immunological abnormalities in splenic marginal zone cell lymphoma". Am. J. Hematol. 56 (3): 173–178. doi:10.1002/(SICI)1096-8652(199711)56:3<173::AID-AJH7>3.0.CO;2-V. PMID 9371530. 
  4. ^ Larking-Pettigrew M, Ranich T, Kelly R (1999). "Rapid onset monoclonal gammopathy in cutaneous lupus erythematosus: interference with complement C3 and C4 measurement". Immunol. Invest. 28 (4): 269–276. doi:10.3109/08820139909060861. PMID 10454004. 
  5. ^ Czaplinski A, Steck A (2004). "Immune mediated neuropathies--an update on therapeutic strategies". J. Neurol. 251 (2): 127–137. doi:10.1007/s00415-004-0323-5. PMID 14991345. 
  6. ^ Sykes, David B.; Schroyens, Wilfried; O'Connell, Casey (2011). "TEMPI Syndrome – A Novel Multisystem Disease". N Engl J Med 365 (5): 475–477. doi:10.1056/NEJMc1106670. PMID 21812700. 
  7. ^ Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E, Sanderson R, Yang Y, Wilson C, Zangari M, Anaissie E, Morris C, Muwalla F, van Rhee F, Fassas A, Crowley J, Tricot G, Barlogie B, Shaughnessy J (2002). "Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells". Blood 99 (5): 1745–1757. doi:10.1182/blood.V99.5.1745. PMID 11861292. 
  8. ^ Magrangeas F, Nasser V, Avet-Loiseau H, Loriod B, Decaux O, Granjeaud S, Bertucci F, Birnbaum D, Nguyen C, Harousseau J, Bataille R, Houlgatte R, Minvielle S (2003). "Gene expression profiling of multiple myeloma reveals molecular portraits in relation to the pathogenesis of the disease". Blood 101 (12): 4998–5006. doi:10.1182/blood-2002-11-3385. PMID 12623842. 
  9. ^ Ocqueteau M, Orfao A, Almeida J, Bladé J, González M, García-Sanz R, López-Berges C, Moro M, Hernández J, Escribano L, Caballero D, Rozman M, San Miguel J (1998). "Immunophenotypic characterization of plasma cells from monoclonal gammopathy of undetermined significance patients. Implications for the differential diagnosis between MGUS and multiple myeloma". Am J Pathol 152 (6): 1655–65. PMC 1858455. PMID 9626070. 
  10. ^ Bladé J (2006). "Clinical practice. Monoclonal gammopathy of undetermined significance". N Engl J Med 355 (26): 2765–2770. doi:10.1056/NEJMcp052790. PMID 17192542. 
  11. ^ Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, Dispenzieri A, Katzmann JA, Melton LJ 3rd. (28 December 2006). "Prevalence of monoclonal gammopathy of undetermined significance". N Engl J Med 354 (13): 1362–1369. doi:10.1056/NEJMoa054494. PMID 16571879. 
  12. ^ Landgren O, Katzmann JA, Hsing AW, Pfeiffer RM, Kyle RA, Yeboah ED, Biritwum RB, Tettey Y, Adjei AA, Larson DR, Dispenzieri A, Melton LJ 3rd, Goldin LR, McMaster ML, Caporaso NE, Rajkumar SV. (Dec 2007). "Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana". Mayo Clin Proc 82 (12): 1468–1473. doi:10.4065/82.12.1468. PMID 18053453. 
  13. ^ Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV. (28 May 2009). "Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study". Blood 113 (22): 5412–7. doi:10.1182/blood-2008-12-194241. PMC 2689042. PMID 19179464. 

Further reading[edit]

  • Weiss, BM; Kuehl, WM (Apr 2010). "Advances in understanding monoclonal gammopathy of undetermined significance as a precursor of multiple myeloma.". Expert review of hematology 3 (2): 165–74. doi:10.1586/ehm.10.13. PMC 2869099. PMID 20473362. 
  • Pérez-Persona, E; Vidriales, MB; Mateo, G; García-Sanz, R; Mateos, MV; de Coca, AG; Galende, J; Martín-Nuñez, G; Alonso, JM; de Las Heras, N; Hernández, JM; Martín, A; López-Berges, C; Orfao, A; San Miguel, JF (Oct 1, 2007). "New criteria to identify risk of progression in monoclonal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter flow cytometry analysis of bone marrow plasma cells.". Blood 110 (7): 2586–92. doi:10.1182/blood-2007-05-088443. PMID 17576818.  Cite uses deprecated parameter |coauthors= (help)
  • Barlogie, B; van Rhee, F; Shaughnessy JD, Jr; Epstein, J; Yaccoby, S; Pineda-Roman, M; Hollmig, K; Alsayed, Y; Hoering, A; Szymonifka, J; Anaissie, E; Petty, N; Kumar, NS; Srivastava, G; Jenkins, B; Crowley, J; Zeldis, JB (Oct 15, 2008). "Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease.". Blood 112 (8): 3122–5. doi:10.1182/blood-2008-06-164228. PMC 2569167. PMID 18669874.  Cite uses deprecated parameter |coauthors= (help)
  • Rossi, F; Petrucci, MT; Guffanti, A; Marcheselli, L; Rossi, D; Callea, V; Vincenzo, F; De Muro, M; Baraldi, A; Villani, O; Musto, P; Bacigalupo, A; Gaidano, G; Avvisati, G; Goldaniga, M; Depaoli, L; Baldini, L (Jul 1, 2009). "Proposal and validation of prognostic scoring systems for IgG and IgA monoclonal gammopathies of undetermined significance.". Clinical cancer research : an official journal of the American Association for Cancer Research 15 (13): 4439–45. doi:10.1158/1078-0432.CCR-08-3150. PMID 19509142.  Cite uses deprecated parameter |coauthors= (help)
  • Golombick, T; Diamond, TH; Badmaev, V; Manoharan, A; Ramakrishna, R (Sep 15, 2009). "The potential role of curcumin in patients with monoclonal gammopathy of undefined significance--its effect on paraproteinemia and the urinary N-telopeptide of type I collagen bone turnover marker.". Clinical cancer research : an official journal of the American Association for Cancer Research 15 (18): 5917–22. doi:10.1158/1078-0432.CCR-08-2217. PMID 19737963. 
  • Rajkumar, SV (Sep 15, 2009). "Prevention of progression in monoclonal gammopathy of undetermined significance.". Clinical cancer research : an official journal of the American Association for Cancer Research 15 (18): 5606–8. doi:10.1158/1078-0432.CCR-09-1575. PMC 2759099. PMID 19737944. 
  • Berenson, JR; Anderson, KC; Audell, RA; Boccia, RV; Coleman, M; Dimopoulos, MA; Drake, MT; Fonseca, R; Harousseau, JL; Joshua, D; Lonial, S; Niesvizky, R; Palumbo, A; Roodman, GD; San-Miguel, JF; Singhal, S; Weber, DM; Zangari, M; Wirtschafter, E; Yellin, O; Kyle, RA (Jul 2010). "Monoclonal gammopathy of undetermined significance: a consensus statement.". British journal of haematology 150 (1): 28–38. doi:10.1111/j.1365-2141.2010.08207.x. PMID 20507313.  Cite uses deprecated parameter |coauthors= (help)
  • Kyle, RA; Durie, BG; Rajkumar, SV; Landgren, O; Blade, J; Merlini, G; Kröger, N; Einsele, H; Vesole, DH; Dimopoulos, M; San Miguel, J; Avet-Loiseau, H; Hajek, R; Chen, WM; Anderson, KC; Ludwig, H; Sonneveld, P; Pavlovsky, S; Palumbo, A; Richardson, PG; Barlogie, B; Greipp, P; Vescio, R; Turesson, I; Westin, J; Boccadoro, M; International Myeloma Working, Group (Jun 2010). "Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management.". Leukemia 24 (6): 1121–7. doi:10.1038/leu.2010.60. PMID 20410922.  Cite uses deprecated parameter |coauthors= (help)