Skip to main content

Advertisement

SpringerLink
Log in

Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum monoclonal (M) protein level less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of hypercalcemia, renal insufficiency, anemia, or bone lesions attributable to a clonal plasma cell disorder. Patients may be tested for a monoclonal gammopathy by serum protein electrophoresis, immunofixation, and the free light chain (FLC) assay. The prevalence of MGUS is 3% for persons more than 50 years of age and 5% in those more than 70 years of age. The risk of progression to multiple myeloma or a related disorder is 1% per year. The size and type of M protein, the number of bone marrow plasma cells, and the results of the FLC ratio are independent risk factors for progression. Smoldering multiple myeloma (SMM) is a more advanced premalignant phase than MGUS and is characterized by more than 3 g/dL of serum M protein, more than 10% clonal plasma cells in the bone marrow, or both, with no evidence of end-organ damage.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Kyle RA: Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med 1978, 64:814–826.

    Article  CAS  PubMed  Google Scholar 

  2. Katzmann JA, Dispenzieri A, Kyle RA, et al.: Elimination of the need for urine studies in the screening algorithm for monoclonal gammopathies by using serum immunofixation and free light chain assays. Mayo Clin Proc 2006, 81:1575–1578.

    Article  CAS  PubMed  Google Scholar 

  3. • Katzmann JA, Kyle RA, Benson J, et al.: Screening panels for detection of monoclonal gammopathies. Clin Chem 2009, 55:1517. Serum protein electrophoresis and the serum FLC assay detected 100% of patients with multiple myeloma or WM and 99.5% of those with SMM.

  4. Axelsson U, Bachmann R, Hallen J: Frequency of pathological proteins (M-components) in 6,995 sera from an adult population. Acta Med Scand 1966, 179:235–247.

    CAS  PubMed  Google Scholar 

  5. Kyle RA, Finkelstein S, Elveback LR, Kurland LT: Incidence of monoclonal proteins in a Minnesota community with a cluster of multiple myeloma. Blood 1972, 40:719–724.

    CAS  PubMed  Google Scholar 

  6. Saleun JP, Vicariot M, Deroff P, Morin JF: Monoclonal gammopathies in the adult population of Finistere, France. J Clin Pathol 1982, 35:63–68.

    Article  CAS  PubMed  Google Scholar 

  7. Kyle RA, Therneau TM, Rajkumar SV, et al.: Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med 2006, 354:1362–1369.

    Article  CAS  PubMed  Google Scholar 

  8. Crawford J, Eye MK, Cohen HJ: Evaluation of monoclonal gammopathies in the “well” elderly. Am J Med 1987, 82:39–45.

    Article  CAS  PubMed  Google Scholar 

  9. Cohen HJ, Crawford J, Rao MK, et al.: Racial differences in the prevalence of monoclonal gammopathy in a community-based sample of the elderly. [Erratum appears in Am J Med 1998, 105(4):362.] Am J Med 1998, 104:439–444.

    Article  CAS  PubMed  Google Scholar 

  10. 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, 107:904–906.

    Article  CAS  PubMed  Google Scholar 

  11. Landgren O, Katzmann JA, Hsing AW, et al.: Prevalence of monoclonal gammopathy of undetermined significance among men in Ghana. Mayo Clin Proc 2007, 82:1468–1473.

    Article  PubMed  Google Scholar 

  12. Iwanaga, M, Tagawa M, Tsukasaki K, et al.: Prevalence of monoclonal gammopathy of undetermined significance: study of 52,802 persons in Nagasaki City, Japan. Mayo Clin Proc 2007, 82:1474–1479.

    Article  Google Scholar 

  13. • 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, 114:785–790. The relative risk of MGUS in relatives of multiple myeloma patients was increased twofold, whereas the risk in relatives of MGUS patients was increased 3.3-fold. This suggests a shared environmental or genetic defect.

  14. • Iwanaga M, Tagawa M, Tsukasaki K, et al.: Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors. Blood 2009, 113:1639–1650. This is the first paper describing the relationship between MGUS and radiation exposure in the Nagasaki atomic bomb explosion. It indicates that only those who were exposed when less than 20 years of age or those who were within 1.5 km of the explosion had an increased risk of MGUS.

  15. • Kyle RA, Rajkumar SV: Epidemiology of the plasma-cell disorders. Best Pract Res Clin Haematol 2007, 20:637–64. This is a comprehensive review of the epidemiology of multiple myeloma and related disorders.

  16. • Landgren O, Kyle RA, Hoppin JA, et al.: Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study. Blood 2009, 113:6386–6391. Agricultural workers who are exposed to insecticides, herbicides, and fungicides have a 1.9-fold higher risk of MGUS than a normal population.

  17. Kyle RA, Therneau TM, Rajkumar SV, et al.: A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med 2002, 346:564–569.

    Article  PubMed  Google Scholar 

  18. Axelsson U: A 20-year follow-up study of 64 subjects with M-components. Acta Med Scand 1986, 219:519–522.

    CAS  PubMed  Google Scholar 

  19. Blade J, Lopez-Guillermo A, Rozman C, et al.: Malignant transformation and life expectancy in monoclonal gammopathy of undetermined significance. Br J Haematol 1992, 81:391–394.

    Article  CAS  PubMed  Google Scholar 

  20. Baldini L, Guffanti A, Cesana BM, et al.: Role of different hematologic variables in defining the risk of malignant transformation in monoclonal gammopathy. Blood 1996, 87:912–918.

    CAS  PubMed  Google Scholar 

  21. Gregersen H, Ibsen J, Mellemkjoer L, et al.: Mortality and causes of death in patients with monoclonal gammopathy of undetermined significance. Br J Haematol 2001, 112:353–357.

    Article  CAS  PubMed  Google Scholar 

  22. Gregersen H, Mellemkjaer L, Salling Ibsen J, et al.: Cancer risk in patients with monoclonal gammopathy of undetermined significance. Am J Hematol 2000, 63:1–6.

    Google Scholar 

  23. Ogmundsdóttir HM, Haraldsdóttir V, M Jóhannesson G, et al.: Monoclonal gammopathy in Iceland: a population-based registry and follow-up. Br J Haematol 2002, 118:166–173.

  24. Avet-Loiseau H, Li JY, Facon T, et al.: High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies. Cancer Res 1998, 58:5640–5645.

    CAS  PubMed  Google Scholar 

  25. Avet-Loiseau H, Facon T, Daviet A, et al.: 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myélome. Cancer Res 1999, 59:4546–4550.

    CAS  Google Scholar 

  26. Fonseca R, Bailey RJ, Ahmann GJ, et al.: Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood 2002, 100:1417–1424.

    CAS  PubMed  Google Scholar 

  27. Chng WJ, Van Wier SA, Ahmann GJ, et al.: A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood 2005, 106:2156–2161.

    Article  CAS  PubMed  Google Scholar 

  28. • Anguiano A, Tuchman SA, Acharya C, et al.: Gene expression profiles of tumor biology provide a novel approach to prognosis and may guide the selection of therapeutic targets in multiple myeloma. J Clin Oncol 2009, 27:4197–4203. This is an excellent article on gene expression profiling, a technique that will be of greater significance in the future.

  29. Rajkumar SV, Mesa RA, Fonseca R, et al.: Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res 2002, 8:2210–2216.

    PubMed  Google Scholar 

  30. Melton LJ 3rd, Rajkumar SV, Khosla S, et al.: Fracture risk in monoclonal gammopathy of undetermined significance. J Bone Miner Res 2004, 19:25–30.

    Article  PubMed  Google Scholar 

  31. Cesana C, Klersy C, Barbarano L, et al.: Prognostic factors for malignant transformation in monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. J Clin Oncol 2002, 20:1625–1634.

    Article  PubMed  Google Scholar 

  32. Rajkumar SV, Kyle RA, Therneau TM, et al.: Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005, 106:812–817.

    Article  CAS  PubMed  Google Scholar 

  33. •• 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, 84:685–693. This is the first report of disease associations in a large number of patients with MGUS. It serves as a guide for determining the importance of clinical entities associated with MGUS.

  34. Kyle RA, Rajkumar SV: Monoclonal gammopathy of undetermined significance. Br J Haematol 2006, 134:573–589.

    Article  CAS  PubMed  Google Scholar 

  35. • Landgren O, Kyle RA, Pfeiffer RM, et al.: Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood 2009, 113:5412–5417. Virtually all patients with multiple myeloma have a preceding MGUS.

  36. Weiss BM, Abadie J, Verma P, et al.: A monoclonal gammopathy precedes multiple myeloma in most patients. Blood 2009, 113:5418–5422.

    Article  CAS  PubMed  Google Scholar 

  37. •• Kyle RA, Remstein ED, Therneau TM, et al.: Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med 2007, 356:2582–2590. This is a long-term follow-up of a large series of patients with SMM. The risk of progression was 10% per year for the first 5 years but fell to 1% to 2% annually after 10 years of observation.

  38. Rosinol L, Blade J, Esteve J, et al.: Smoldering multiple myeloma: natural history and recognition of an evolving type. Br J Haematol 2003, 123:631–636.

    Article  CAS  PubMed  Google Scholar 

  39. Witzig TE, Kyle RA, O’Fallon WM, Greipp PR: Detection of peripheral blood plasma cells as a predictor of disease course in patients with smouldering multiple myeloma. Br J Haematol 1994, 87:266–272.

    Article  CAS  PubMed  Google Scholar 

  40. Weber DM, Dimopoulos MA, Moulopoulos LA, et al.: Prognostic features of asymptomatic multiple myeloma. Br J Haematol 1997, 97:810–814.

    Article  CAS  PubMed  Google Scholar 

  41. Dispenzieri A, Kyle RA, Katzmann JA, et al.: Immunoglobulin free light chain ratio is an independent risk factor for progression of smoldering (asymptomatic) multiple myeloma. Blood 2008, 111:785–789.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

Supported in part by research grants CA 62242 and CA107476 by the National Institutes of Health, Bethesda, Maryland, USA.

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Department of Medicine, Laboratory Medicine & Pathology, College of Medicine Mayo Clinic, Stabile 6-28, 200 First Street SW, Rochester, MN, 55905, USA

    Robert A. Kyle & S. Vincent Rajkumar

Authors
  1. Robert A. Kyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S. Vincent Rajkumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert A. Kyle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kyle, R.A., Rajkumar, S.V. Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma. Curr Hematol Malig Rep 5, 62–69 (2010). https://doi.org/10.1007/s11899-010-0047-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-010-0047-9

Keywords

Search

Navigation