eMedicine Specialties > Hematology > Plasma Cell Disorders

Monoclonal Gammopathies of Uncertain Origin

Author: Suzanne R Fanning, DO, Fellow, Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, 2004-2007 Director, Hematology, Greenville Memorial Health System, Greenville, SC Medical Oncologist/Hematologist/Transplant Physician, Cancer Centers of the Carolinas
Coauthor(s): Mohamad A Hussein, MD, Clinical Director, Malignant Hematology, Moffitt Cancer Center
Contributor Information and Disclosures

Updated: Aug 29, 2009

Introduction

Background

Monoclonal gammopathy of undetermined significance (MGUS) is the most common of a spectrum of diseases called plasma cell dyscrasias. The term MGUS denotes the presence of a monoclonal immunoglobulin (Ig), also called an M-protein, in the serum or urine in persons without evidence of multiple myeloma (MM), Waldenström macroglobulinemia (WM), amyloidosis (AL) or other lymphoproliferative disorders.1 MM is a uniformly lethal disease that varies from a disease that does not need therapy at first to an advanced or aggressive stage that requires therapy. Distinguishing between MM and MGUS is critical because patients with MGUS are conservatively treated and do not need chemotherapy.

Pathophysiology

The reason for the monoclonal expansion of a single Ig-secreting plasma cell population in what appears to be a nonmalignant manner is unknown in most cases. Most cases involve IgG or IgA monoclonal cell populations. About 15-20% are composed of IgM monoclonal cells.

Kyle et al reported that the cells in IgG and IgA MGUS arise from a mature, somatically mutated, postswitch plasma cell. About 50% of cases have evidence of translocation in the Ig heavy-chain region at 14q32. In contrast, IgM MGUS is described as arising from somatically mutated, postgerminal center B lymphocytes that have not undergone isotype class switching and therefore do not have the 14q32 translocation. These translocations are thought to be important in initiating and sustaining clonal proliferation.2

Several studies have confirmed that characteristic genetic abnormalities of multiple myeloma are present in patients with MGUS.3,4,5 Gene-expression profiling has also led to a group with MGUS-like features. This group of patients had a lower complete remission rate, yet also had a lower-risk clinical course and superior survival.6

The risk of progression to MM or other lymphoproliferative disorder is present at a constant rate throughout the remainder of a patient's life. This observation suggests that the second event responsible for progression is a random event and not cumulative.

Frequency

United States

MGUS represents two thirds of all plasma cell dyscrasias. The incidence increases with age. MGUS occurs in up to 5.3% of the population older than 70 years.7

International

International frequency is the same as stated in US frequency.

Mortality/Morbidity

  • Patients with MGUS tend to do well when treated conservatively.
  • Regular surveillance is required to assess for progression to either a lymphoproliferative disorder or to MM.8  This risk has been quantified at 1% per year.7

Race

A retrospective study by the Veterans Administration revealed that the age-adjusted prevalence ratio of MGUS in black patients was 3.0 compared with white patients.9 For a discussion of possible genetic factors in the pathogenesis of monoclonal gammopathy of undetermined significance, see Landgren et al.9,10

Sex

The disease is more prevalent in men than in women, and the prognosis for men was worse than that of women in some studies.

Age

  • The median age of patients with the disease is 70 years; however, most physicians are observing patients younger than this, possibly because of improved screening rather than an increased incidence of the process.
  • The incidence of MGUS is higher in older patients than in younger patients. Of patients older than 80 years, the available literature suggests as many as 10-15% may have an M-protein.

Clinical

History

  • The finding of MGUS is usually an unexpected event during an evaluation for an unrelated disorder.
  • The advances in quantification of an M-spike by immunofixation contribute to the increasing number of patients identified as having MGUS.
  • MGUS is characterized by the following:
    • Serum M-protein value less than 3 g/dL
    • Fewer than 10% plasma cells in the bone marrow
    • No or only small amounts of Bence-Jones protein in the urine
    • Absence of lytic bone lesions
    • No related anemia, hypercalcemia, renal failure, or any related end-organ damage

Physical

  • No specific abnormalities are detected on physical examination in patients with MGUS.
  • Several syndromes of polyneuropathies are associated with plasma cell dyscrasias, including MGUS.

Causes

The cause of MGUS is unknown, though the same theories that apply to the pathogenesis of MM may be valid in MGUS.

More on Monoclonal Gammopathies of Uncertain Origin

Overview: Monoclonal Gammopathies of Uncertain Origin
Differential Diagnoses & Workup: Monoclonal Gammopathies of Uncertain Origin
Treatment & Medication: Monoclonal Gammopathies of Uncertain Origin
Follow-up: Monoclonal Gammopathies of Uncertain Origin
References
Further Reading
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References

  1. 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. Aug 2009;84(8):685-93. [Medline]. [Full Text].

  2. Kyle RA, Therneau TM, Rajkumar SV, et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood. Nov 15 2003;102(10):3759-64. [Medline].

  3. Kaufmann H, Ackermann J, Baldia C, et al. Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolove during transition to multiple myeloma. Leukemia. 2004;18:1879-1882.

  4. Chang WJ, Van Wier SA, Ahmann GJ, et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood. Sep 15 2005;106(6):2156-61.

  5. Ogmundsdottir HM, Einarsdottir HK, Steingrimsdottir H, Haraldsdottir V. Familial predisposition to monoclonal gammopathy of unknown significance, Waldenstrom's macroglobulinemia, and multiple myeloma. Clin Lymphoma Myeloma. Mar 2009;9(1):27-9. [Medline].

  6. Fenhuang Z, Barlogie B, Arzoumanian, et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myelom is linked to good prognosis. Blood. 2007;109:1692-1700.

  7. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. Feb 21 2002;346(8):564-9. [Medline].

  8. Kristinsson SY, Bjorkholm M, Andersson TM, et al. Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance (MGUS): a population-based study. Haematologica. Jul 16 2009;epub ahead of print. [Medline]. [Full Text].

  9. 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. Feb 1 2006;107(3):904-6.

  10. Landgren O, Weiss BM. Patterns of monoclonal gammopathy of undetermined significance and multiple myeloma in various ethnic/racial groups: support for genetic factors in pathogenesis. Leukemia. Jul 9 2009;[Medline].

  11. Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. Aug 2009;55(8):1517-22. [Medline].

  12. Ng AP, Wei A, Bhurani D, et al. The sensitivity of CD138 immunostaining of bone marrow trephine specimens for quantifying marrow involvement in MGUS and myeloma, including samples with a low percentage of plasma cells. Haematologica. 2006;91:972-975.

  13. Jerez A, Ortuno FJ, Osma MD, et al. Bone-marrow immunophenotypic analysis allows the identification of high risk of progression and immune condition-related monoclonal gammopathy of undetermined significance. Ann Med. Jul 26 2009;1-12. [Medline].

  14. Rajkumar SV. MGUS and Smoldering Multiple Myeloma: Update on Pathogenesis, Natural History, and Management. Hematology (Am Soc Hematol Educ Program). 2005;340-5.

  15. Cohen AL, Sarid R. The relationship between monoclonal gammopathy of undetermined significance and venous thromboembolic disease. Thromb Res. Feb 2 2009;[Medline].

  16. Srkalovic G, Cameron MG, Rybicki L, et al. Monoclonal gammopathy of undetermined significance and multiple myeloma are associated with an increased incidence of venothromboembolic disease. Cancer. Aug 1 2004;101(3):558-66.

  17. 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. Aug 1 2005;106(3):812-7.

  18. Davies FE, Dring AM, Li C, et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood. Dec 15 2003;102(13):4504-11.

  19. Decaux O, Laurat E, Perlat A, et al. Systemic manifestations of monoclonal gammopathy. Eur J Intern Med. Sep 2009;20(5):457-61. [Medline].

  20. Feinman R, Sawyer J, Hardin J, Tricot G. Cytogenetics and molecular genetics in multiple myeloma. Hematol Oncol Clin North Am. Feb 1997;11(1):1-25. [Medline].

  21. Fonesca R, Bailey RJ, Ahmann GJ, et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002;100:1417-1424.

  22. Korac P, Peran I, Skrtic A, et al. FOXP1 expression in monoclonal gammopathy of undetermined significance and multiple myeloma. Pathol Int. May 2009;59(5):354-8. [Medline].

  23. Kumar S, Rajkumar SV, Kyle RA, et al. Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance. J Clin Oncol. Aug 20 2005;23(24):5668-74.

  24. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. New England Journal of Medicine. 2006;354:1362-1369.

  25. Madan S, Greipp PR. The incidental monoclonal protein: Current approach to management of monoclonal gammopathy of undetermined significance (MGUS). Blood Rev. Aug 19 2009;epub ahead of print. [Medline].

  26. Niermeijer JM, Eurelings M, Lokhorst HL, et al. Rituximab for polyneuropathy with IgM monoclonal gammopathy. J Neurol Neurosurg Psychiatry. Sep 2009;80(9):1036-9. [Medline].

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Further Reading

Related eMedicine Topics

Clinical Trials
 National Guideline Clearinghouse

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Keywords

monoclonal gammopathy of undetermined significance, MGUS, multiple myeloma, MM, AL amyloidosis, plasma cell dyscrasias, Waldenström macroglobulinemia, WM, other lymphoproliferative disorders

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Contributor Information and Disclosures

Author

Suzanne R Fanning, DO, Fellow, Department of Hematology and Medical Oncology, Cleveland Clinic Foundation, 2004-2007 Director, Hematology, Greenville Memorial Health System, Greenville, SC Medical Oncologist/Hematologist/Transplant Physician, Cancer Centers of the Carolinas
Suzanne R Fanning, DO is a member of the following medical societies: American College of Physicians, American Medical Association, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, and American Society of Hematology
Disclosure: Millenium Pharmaceuticals Consulting fee Review panel membership; Celgene Pharmaceuticals Consulting fee Review panel membership

Coauthor(s)

Mohamad A Hussein, MD, Clinical Director, Malignant Hematology, Moffitt Cancer Center
Mohamad A Hussein, MD is a member of the following medical societies: American Association of Blood Banks, American College of Physicians, American Medical Association, and American Society of Hematology
Disclosure: Nothing to disclose.

Medical Editor

Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Karen Seiter, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, and American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching; Schering Honoraria Speaking and teaching; Cephalon Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center
Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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