Diagnostic Considerations

Monoclonal gammopathy of undetermined significance (MGUS) must be differentiated from myoclonal gammopathy of renal significance (MGRS), multiple myeloma (MM), and smoldering MM (SMM). Criteria for MGUS established by the International Myeloma Working Group^[32]and the World Health Organization^[33]are as follows:

Serum M-protein level < 3 g/dL
Bone marrow plasma cells < 10% and low level of plasma cell infiltration in a trephine biopsy specimen
No evidence of B-cell proliferative disorder (ie, MM, Waldenström macroglobulinemia, amyloid light-chain amyloidosis)
No M-protein or only small amounts of monoclonal light chain in urine
No osteolytic lesions, anemia, hypercalcemia, or M-protein–related renal function impairment

In addition to the hematologic abnormalities, MGRS is associated with a wide spectrum of renal diseases, including AL amyloidosis, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases of MGRS, to identify the exact lesion and determine its severity.^[5]Treatment to eradicate the underlying clone is indicated; the proteasome inhibitor bortezomib is the preferred therapy in MGRS but a number of other agents have been used in some settings, including rituximab, cytotoxic chemotherapy, and immunomodulatory agents.^[34]

Asymptomatic patients who have an M-component higher than 3 g/dL, or more than 10% but less than 20% bone marrow plasma cells, fulfill the criteria for SMM. These patients do not have anemia, renal failure, hypercalcemia, osteolytic bone lesions, or other clinical manifestations related to the monoclonal protein.

In clinical and biologic terms, SMM is closer to MGUS than to overt MM. Recognition of patients with SMM is extremely important because they should not be treated with chemotherapy until progression occurs. No particular laboratory parameter or clinical factor differentiates MGUS or SMM from overt MM. Decreased levels of uninvolved immunoglobulins are not a useful criteria for differentiation because 30-40% of patients with MGUS also have decreased levels of the uninvolved immunoglobulins.

Although Bence-Jones proteinuria suggests MM, finding small amounts of monoclonal light chains in the urine of patients with MGUS is not unusual. Lytic bone lesions on the skeletal survey strongly suggest MM. In patients recently diagnosed with MGUS, serum electrophoresis should be repeated after 3 months to exclude early myeloma, and, if the results are stable, the test should be repeated in 6 months. Patients should be aware that the evolution of MGUS to MM can be abrupt; therefore, they should be reexamined promptly if their clinical condition deteriorates.

Differential Diagnoses

Workup

Bida JP, Kyle RA, Therneau TM, Melton LJ 3rd, Plevak MF, Larson DR, et al. Disease associations with monoclonal gammopathy of undetermined significance: a population-based study of 17,398 patients. Mayo Clin Proc. 2009 Aug. 84(8):685-93. [Medline]. [Full Text].
Uddin Z, Maennle D, Russell K, Boltri JM. Monoclonal gammopathy of undetermined significance: Using risk stratification to guide follow-up. J Fam Pract. 2015 Jul. 64 (7):E5-E12. [Medline]. [Full Text].
[Guideline] van de Donk NW, Palumbo A, Johnsen HE, Engelhardt M, Gay F, 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. [Medline]. [Full Text].
Leung N, Bridoux F, Hutchison CA, Nasr SH, Cockwell P, Fermand JP, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012 Nov 22. 120 (22):4292-5. [Medline].
Bridoux F, Leung N, Hutchison CA, Touchard G, Sethi S, Fermand JP, et al. Diagnosis of monoclonal gammopathy of renal significance. Kidney Int. 2015 Apr. 87 (4):698-711. [Medline]. [Full Text].
Kyle RA, Therneau TM, Rajkumar SV, et al. Long-term follow-up of IgM monoclonal gammopathy of undetermined significance. Blood. 2003 Nov 15. 102(10):3759-64. [Medline].
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.
Chang WJ, Van Wier SA, Ahmann GJ, et al. A validated FISH trisomy index demonstrates the hyperdiploid and nonhyperdiploid dichotomy in MGUS. Blood. 2005 Sep 15. 106(6):2156-61.
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. 2009 Mar. 9(1):27-9. [Medline].
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.
Nagoshi H, Taki T, Chinen Y, Tatekawa S, Tsukamoto T, Maegawa S, et al. Transcriptional dysregulation of the deleted in colorectal carcinoma gene in multiple myeloma and monoclonal gammopathy of undetermined significance. Genes Chromosomes Cancer. 2015 Dec. 54 (12):788-95. [Medline].
Mullikin TC, Rajkumar SV, Dispenzieri A, Buadi FK, Lacy MQ, Lin Y, et al. Clinical characteristics and outcomes in biclonal gammopathies. Am J Hematol. 2016 May. 91 (5):473-5. [Medline].
Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006 Mar 30. 354 (13):1362-9. [Medline]. [Full Text].
Murray D, Kumar SK, Kyle RA, Dispenzieri A, Dasari S, Larson DR, et al. Detection and prevalence of monoclonal gammopathy of undetermined significance: a study utilizing mass spectrometry-based monoclonal immunoglobulin rapid accurate mass measurement. Blood Cancer J. 2019 Dec 13. 9 (12):102. [Medline]. [Full Text].
Genet P, Sutton L, Chaoui D, Al Jijakli A, Gerbe J, Masse V, et al. Prevalence of monoclonal gammopathy in HIV patients in 2014. J Int AIDS Soc. 2014. 17(4 Suppl 3):19649. [Medline]. [Full Text].
Landgren O, Shim YK, Michalek J, Costello R, Burton D, Ketchum N, et al. Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study. JAMA Oncol. 2015 Nov 1. 1 (8):1061-8. [Medline].
Landgren O, Zeig-Owens R, Giricz O, Goldfarb D, Murata K, Thoren K, et al. Multiple Myeloma and Its Precursor Disease Among Firefighters Exposed to the World Trade Center Disaster. JAMA Oncol. 2018 Jun 1. 4 (6):821-827. [Medline].
Kristinsson SY, Björkholm M, Landgren O. Survival in monoclonal gammopathy of undetermined significance and waldenström macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2013 Apr. 13(2):187-90. [Medline].
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. 2009 Jul 16. epub ahead of print. [Medline]. [Full Text].
Kyle RA, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Cerhan JR, et al. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med. 2018 Jan 18. 378 (3):241-249. [Medline]. [Full Text].
Landgren O, Gridley G, Turesson I, Caporaso NE, Goldin LR, Baris D, 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 Feb 1. 107 (3):904-6. [Medline]. [Full Text].
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. 2009 Jul 9. [Medline].
Rajkumar SV, Kyle RA, Therneau TM, Melton LJ 3rd, Bradwell AR, Clark RJ, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005 Aug 1. 106 (3):812-7. [Medline]. [Full Text].
Pelzer BW, Arendt M, Moebus S, Eisele L, Jöckel KH, Dührsen U, et al. Light chain monoclonal gammopathy of undetermined significance is characterized by a high disappearance rate and low risk of progression on longitudinal analysis. Ann Hematol. 2018 Aug. 97 (8):1463-1469. [Medline].
Turesson I, Kovalchik SA, Pfeiffer RM, Kristinsson SY, Goldin LR, Drayson MT, et al. Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden. Blood. 2014 Jan 16. 123(3):338-45. [Medline]. [Full Text].
Cohen AL, Sarid R. The relationship between monoclonal gammopathy of undetermined significance and venous thromboembolic disease. Thromb Res. 2009 Feb 2. [Medline].
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. 2004 Aug 1. 101(3):558-66.
Kristinsson SY, Tang M, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study. Blood. 2010 Oct 14. 116(15):2651-5. [Medline].
Piot JM, Royer M, Schmidt-Tanguy A, Hoppé E, Gardembas M, Bourrée T, et al. Factors associated with an increased risk of vertebral fracture in monoclonal gammopathies of undetermined significance. Blood Cancer J. 2015 Aug 28. 5:e345. [Medline].
Kristinsson SY, Tang M, Pfeiffer RM, Björkholm M, Goldin LR, Blimark C, et al. Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study. Haematologica. 2012 Jun. 97 (6):854-8. [Medline]. [Full Text].
Rison RA, Beydoun SR. Paraproteinemic neuropathy: a practical review. BMC Neurol. 2016 Jan 28. 16:13. [Medline]. [Full Text].
[Guideline] Kyle RA, et al; International Myeloma Working Group. 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. 2010 Jun. 24 (6):1121-7. [Medline].
Swerdlow SH, Campro E, Harris NL, et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC; 2008.
D'Souza A. Monoclonal Gammopathy of Renal Significance. American Society of Hematology - Ask The Hematologist. Available at https://www.hematology.org/Thehematologist/Ask/9059.aspx. November-December 2018; Accessed: December 27, 2019.
Katzmann JA, Kyle RA, Benson J, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009 Aug. 55(8):1517-22. [Medline].
Greenberg AJ, Cousin M, Kumar S, Ketterling RP, Knudson RA, Larson D, 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 May 6. [Medline].
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.
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. 2009 Jul 26. 1-12. [Medline].
Go RS, Rajkumar SV. How I manage monoclonal gammopathy of undetermined significance. Blood. 2018 Jan 11. 131 (2):163-173. [Medline].
Sigurdardottir EE, Turesson I, Lund SH, Lindqvist EK, Mailankody S, Korde N, et al. The Role of Diagnosis and Clinical Follow-up of Monoclonal Gammopathy of Undetermined Significance on Survival in Multiple Myeloma. JAMA Oncol. 2015 May. 1 (2):168-74. [Medline].
Mikhael J. Ask the Hematologist: A Diagnostic Approach to Patients with an IgM monoclonal protein. American Society of Hematology. Available at http://www.hematology.org/Thehematologist/Ask/3186.aspx. August 3, 2016; Accessed: December 27, 2019.
Niermeijer JM, Eurelings M, Lokhorst HL, et al. Rituximab for polyneuropathy with IgM monoclonal gammopathy. J Neurol Neurosurg Psychiatry. 2009 Sep. 80(9):1036-9. [Medline].
Castaneda-Avila MA, Ulbricht CM, Epstein MM. Risk factors for monoclonal gammopathy of undetermined significance: a systematic review. Ann Hematol. 2021 Apr. 100 (4):855-863. [Medline]. [Full Text].
Hofmann JN, Beane Freeman LE, Murata K, Andreotti G, Shearer JJ, Thoren K, et al. Lifetime Pesticide Use and Monoclonal Gammopathy of Undetermined Significance in a Prospective Cohort of Male Farmers. Environ Health Perspect. 2021 Jan. 129 (1):17003. [Medline]. [Full Text].
Baldursdóttir TR, Löve ÞJ, Gíslason GK, Björkholm M, Mellqvist UH, Lund SH, et al. Autoimmune disease is associated with a lower risk of progression in monoclonal gammopathy of undetermined significance. Eur J Haematol. 2021 Mar. 106 (3):380-388. [Medline].
Pang L, Rajkumar SV, Kapoor P, Buadi F, Dispenzieri A, Gertz M, et al. Prognosis of young patients with monoclonal gammopathy of undetermined significance (MGUS). Blood Cancer J. 2021 Feb 1. 11 (2):26. [Medline]. [Full Text].
Castillo JJ, Callander NS, Baljevic M, Sborov DW, Kumar S. The evaluation and management of monoclonal gammopathy of renal significance and monoclonal gammopathy of neurological significance. Am J Hematol. 2021 Jul 1. 96 (7):846-853. [Medline]. [Full Text].
Dispenzieri A. Monoclonal gammopathies of clinical significance. Hematology Am Soc Hematol Educ Program. 2020 Dec 4. 2020 (1):380-388. [Medline]. [Full Text].
Jain A, Haynes R, Kothari J, Khera A, Soares M, Ramasamy K. Pathophysiology and management of monoclonal gammopathy of renal significance. Blood Adv. 2019 Aug 13. 3 (15):2409-2423. [Medline]. [Full Text].
Georgakopoulou R, Andrikopoulou A, Sergentanis TN, Fiste O, Zagouri F, Gavriatopoulou M, et al. Overweight/Obesity and Monoclonal Gammopathy of Undetermined Significance. Clin Lymphoma Myeloma Leuk. 2021 Jun. 21 (6):361-367. [Medline].
Han JH, Wang JN, Zhang YL, Cao XX, Zhou DB, Xu TD, et al. Prevalence of monoclonal gammopathy of undetermined significance in a large population with annual medical check-ups in China. Blood Cancer J. 2020 Mar 9. 10 (3):34. [Medline]. [Full Text].

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Author

Suzanne R Fanning, DO Director of Hematology, Greenville Memorial Health System; 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, American Society of Hematology

Disclosure: Received consulting fee from Millenium Pharmaceuticals for review panel membership; Received consulting fee from Celgene Pharmaceuticals for 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, American Society of Hematology

Disclosure: Received income in an amount equal to or greater than $250 from: Celgene corporation.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

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, American Society of Hematology

Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.