Monoclonal Gammopathies of Undetermined Significance

Monoclonal Gammopathies of Undetermined Significance

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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]

Immunoglobulin involvement may be IgM, non-IgM (ie, IgA, IgG, or, rarely, IgD or IgE), or light chain. [2] All pose a risk, albeit varying, of progression to a malignant disorder. Typically, IgG and IgA MGUS progress to MM, IgM MGUS progresses to WM or other lymphoproliferative disorders, and light-chain MGUS is the precursor of light-chain MM. [3]

The cause of MGUS is unknown, though the same theories that apply to the pathogenesis of MM may be valid in MGUS. MM is almost always preceded by MGUS. [3]

Distinguishing between MM and MGUS is critical because patients with MGUS are conservatively treated and do not need chemotherapy. In contrast, MM is a uniformly lethal disease that does not need therapy in its initial stages but progresses to an advanced or aggressive stage that requires therapy.

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. [4]

Several studies have confirmed that characteristic genetic abnormalities of multiple myeloma (MM) are present in patients with MGUS. [5, 6, 7] 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. [8]

Nagoshi et al identified a possible secondary genetic change involving MGUS; they found transcriptional dysregulation of the deleted in colorectal carcinoma (DCC) gene in 25% of MGUS cases studied, and in 57% of MM. The DCC gene encodes a tumor suppressor that prevents cell growth; allele loss or decreased expression of DCC has been associated with the progression of solid tumors and hematologic malignancies. [9]

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.

In patients with symptomatic MM, the development of a new monoclonal protein following therapy is associated with better outcomes. A study by Mullikin et al in patients with biclonal gammopathy of undetermined significance found that the rate of progression was similar to that seen in MGUS with one monoclonal protein, suggesting that multiple monoclonal proteins do not clinically impact one another. Of the 393 patients in the study, six progressed to smoldering MM, 11 to MM, three to amyloidosis, and two to Waldenström macroglobulinemia. [10]

MGUS represents two thirds of all plasma cell dyscrasias. The incidence increases with age. In a study of residents of Olmsted County, Minnesota, MGUS was found in 3.2% of persons 50 years of age or older, 5.3% of those 70 years of age or older, and 7.5% of those 85 years of age or older. [11]

The prevalence of MGUS is higher in HIV-infected patients, although it decreased with the adoption of antiretroviral therapy. In a study of 383 French HIV-infected patients, 359 of whom were on antiretroviral therapy for a median duration of 105 months, there were 12 (3.1%) cases of MGUS, including five IgG kappa cases, 5 IgG lambda cases, one biclonal (2 IgG kappa) case, and one case with three monoclonal immunoglobulins (IgG kappa×2+IgG lambda). In all cases, the monoclonal immunoglobulin levels were low, and the level was below 1 g/l in all cases except two. No factors were found to be predictive of MGUS. [12]

In a prospective cohort study in Vietnam war veterans, the crude prevalence of overall MGUS was 7.1% (34 of 479) in veterans involved in the spraying of Agent Orange, versus 3.1% (15 of 479) in veterans who were not involved in herbicide spray missions. After adjustment for factors including age, race, and body mass index, this translated into a 2.4-fold increased risk for MGUS in exposed veterans (adjusted odds ratio, 2.37; 95% CI, 1.27-4.44; P = 0.007). [13]

In a study of firefighters involved in rescue and/or recovery work at the New York World Trade Center after the September 11, 2001 attack, Landdgren et al reported an age-standardized prevalence rate of MGUS and light-chain MGUS combined of 7.63 per 100 persons (95% CI, 5.45-9.81), which is 1.8-fold higher than rates from a reference population; the rate of light-chain MGUS was more than 3-fold higher than in the same reference population. Of the 781 firefighters studied, 16 had been diagnosed with multiple myeloma (7 of them with light-chain disease), at a median age of 57 years. [14]  

Patients with MGUS tend to do well when treated conservatively. [15] Regular surveillance is required to assess for progression to either a lymphoproliferative disorder or to MM. [16] This risk has been quantified at 1% per year. [17]

A retrospective study by the US Department of Veterans Affairs revealed that the age-adjusted prevalence ratio of MGUS in black patients was 3.0 compared with white patients. [18] For a discussion of possible genetic factors in the pathogenesis of MGUS, see Landgren et al. [18, 19]

MGUS occurs more commonly in men than in women, and the prognosis for men was worse than that of women in some studies.

Age-related differences in incidence are as follows:

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

The annual risk of progression to multiple myeloma (MM), Waldenström macroglobulinemia (WM), amyloidosis (AL), or other lymphoproliferative disorders is approximately 1%. However, the mode and risk of progression vary between IgM MGUS and those with non-IgM MGUS. 

An abnormal serum free light-chain ratio (ratio of kappa to lambda free light chains) and a high serum monoclonal protein (M protein) level (≥1.5 g per deciliter) are risk factors for progression. In IgM MGUS, Kyle et al reported a risk of progression at 20 years of 55% in patients with both risk factors, compared with 41% in those with one risk factor and 19% in patients with neither risk factor. In patients with non-IgM MGUS, the risk of progression at 20 years was 30% in those with both risk factors, 20% in those iwth one risk factor, and 7% in those with neither risk factor. [17]

Rajkumar et al found that the risk of progression in patients with an abnormal serum free light chain (FLC) ratio (kappa-lambda ratio <  0.26 or > 1.65) is independent of the size and type of the serum M protein, and that the relative risk of progression is related to the extent to which the ratio is abnormal. These authors proposed a risk-stratification model for the progression of MGUS, using the combination of the size and type of the M protein and the serum FLC ratio. [20]

Pelzer et al concluded that light-chain MGUS—defined as an abnormal FLC ratio, increase of involved FLC with complete loss of immunoglobulin heavy chain, and absence of a history of lymphoproliferative disease—is a relatively benign condition, and that the monoclonal protein often diisappears over time. In their longitudinal analysis of 75 German patients with light-chain MGUS, after a median observation time of 11.5 years, none of the cases had progressed to light-chain multiple myeloma or other lymphoproliferative disorders. On serial analysis, light-chain MGUS could not be confirmed in 17 of 31 cases (55%), and disappearance of the monoclonal protein was associated with low concentrations of the involved FLC. Although patients with light-chain MGUS had a 1.5-fold increased risk of cancer, overall survival and renal function were not different than in patients with normal FLC. [21]

In a study of 728 Swedish MGUS patients followed for up to 30 years, 84 patients developed a lymphoid disorder, representing a cumulative risk of 15.4%. The 30-year cumulative risk for myeloid malignancies was less than 2%. The 30-year cumulative risk for MM, which occurred in 53 patients, was 10.6%, with an approximately 0.5% annual risk. The following factors were significantly associated with progression [22] :

An abnormal FLC ratio of less than 0.26 or more than 1.65

An M-protein concentration of 1.5 g/dL or more

Reduction of one or two noninvolved immunoglobulin isotype levels

The risk of venous thromboembolism (VTE) is increased in patients with MGUS. [23] In a study by Srkalovic et al, 13% of patients with MGUS developed VTE. [24] Univariate correlates of VTE in patients with MGUS included the following:

Family or past history of VTE

Immobility

Low serum albumin level

High leukocyte count

Using population-based data from Sweden, Kristinsson et al compared the risks of fractures in 5,326 patients with MGUS diagnosed from 1958-2006 with 20,161 matched controls. [25] Patients with MGUS had an increased risk of any fracture at 5 years (hazard ratio [HR] = 1.74) and 10 (HR = 1.61) years. The risk was significantly higher for axial (skull, vertebral/pelvis, and sternum/costae) compared with distal (arm and leg) fractures (P< 0.001).

A French study found that, in addition to low bone density, patients with MGUS who experienced nontraumatic vertebral fractures were more likely to have a lambda light chain isotype. In this prospective study of 201 patients with incidentally discovered MGUS and no known history of osteoporosis, nontraumatic vertebral fracture was discovered in 8.4% of the patients, with equal distribution between men and women. Patients with lambda light chain had an odds ratio of 4.32 (95% confidence interval 1.80–11.16; P=0.002) for fracture, compared with patients with kappa light chain. [26]

Kristinsson et al reported that patients with MGUS had a 2-fold increased risk (P < 0.05) of developing any infection. [27] The risk extended to both bacterial and viral infections, and the following specific infections were noted:

Infection risk was highest in patients with M-protein concentrations over 2.5 g/dL, but was also increased in those with concentrations below 0.5 g/dL. Patients with MGUS who developed infections had no excess risk of progression to related malignancy.

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].

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].

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, 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.

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.

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. September 15, 2014; Accessed: December 24, 2015.

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].

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.

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.

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.

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.

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.

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