Prevalence of Monoclonal Gammopathy of Undetermined Significance

Kyle, Robert A.; Therneau, Terry M.; Rajkumar, S. Vincent; Larson, Dirk R.; Plevak, Matthew F.; Offord, Janice R.; Dispenzieri, Angela; Katzmann, Jerry A.; Melton, L. Joseph

doi:10.1056/nejmoa054494

Cited by 1,129 publications

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“…Indeed, AL amyloidosis, the most commonly diagnosed systemic form of amyloid, is not infrequently a diagnosis of exclusion, which is complicated by the fact that there is considerable overlap between the clinical features of the different amyloid types. Furthermore, it is important to recognize that the presence of a plasma cell dyscrasia, which occurs in approximately 3% of the population older than 50 years and approximately 5% of those older than 70 years, 29 in a patient with amyloidosis does not prove AL type and may be incidental to their amyloidosis. 30 The deposits in approximately 20% of patients with AL amyloidosis fail to stain with antibodies against and immunoglobulin light chains, presumably reflecting the fact that the fibrils consist of misfolded, variable light chain domains within which certain epitopes may be masked.…”

Section: Discussionmentioning

confidence: 99%

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Rowczenio

Doğan

Theis

et al. 2011

The American Journal of Pathology

111

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The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as "primary"), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Amyloidosis is a rare disorder characterized by extracellular deposition of fibrillar protein that results in a progressive disruption of structure and function of affected tissues and organs. Amyloidosis is a remarkably heterogeneous disease; it can be acquired or hereditary and systemic or localized.The most common form of systemic amyloidosis is AL (light chain, previously referred to as "primary"), in which the fibrils are derived from monoclonal immunoglobulin light chains and consist of the whole or part of the variable (V L ) domain. The prognosis of systemic AL amyloidosis is generally worse than in other amyloid types, although there is marked heterogeneity in the extent of organ involvement and rate of disease progression. Treatment of AL amyloidosis is with chemotherapy for which there is no role in other amyloid types.Hereditary systemic amyloidosis is a rare autosomal dominant condition caused by deposition of variant proteins as amyloid fibrils. The term "hereditary nonneuropathic systemic amyloidosis" (Online Mendelian Inheritance of Man no. 105200) was coined by Ostertag 1 in 1932 following the discovery of two families with dominantly inherited renal amyloidosis. Mutations in the genes encoding apolipoprotein A-I (apoAI), 2-12 apolipoprotein A-II (apoAII), 13 fibrinogen A␣-chain, 14 -17 and lysozyme 18 have since been identified as the cause of hereditary renal amyloidosis in different kindreds (Online Mendelian Inheritance of Man no. 105200). The clinical amyloidosis syndromes that accompany the various mutations in these different genes are diverse with respect to age at onset, mode of presentation, pattern of organ distribution, rate of progression, and prognosis. Indeed, certain apoAI variants are associated with neuropathy 19,20 such that the nomenclature, which includes the term "nonneuropathic," is confusing and probably no longer appropriate.Supported by the UK Department of Health.Accepted for publication June 15, 2011.The licensed patent rights to perform protein extraction from paraffinembedded tissue for the mass spectrometry-based amyloid typing test were granted by Expression Patholo...

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Section: Discussionmentioning

confidence: 99%

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Rowczenio

Doğan

Theis

et al. 2011

The American Journal of Pathology

111

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“…MGUS is present in over 3% of the population above the age of 50, and progresses to myeloma or related malignancy a rate of 1% per year [11,12]. Since MGUS is asymptomatic, over 50% of individuals who are diagnosed with MGUS have had the condition for over 10 years before the clinical diagnosis [13].…”

Section: Disease Overviewmentioning

confidence: 99%

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

2013

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Disease overviewMultiple myeloma accounts for approximately 10% of hematologic malignancies.DiagnosisThe diagnosis requires 10% or more clonal plasma cells on bone marrow examination or a biopsy proven plasmacytoma plus evidence of associated end‐organ damage. In addition, the presence of 60% or more clonal plasma cells in the marrow is also considered as myeloma regardless of the presence or absence of end‐organ damage.Risk stratificationIn the absence of concurrent trisomies, patients with 17p deletion, t(14;16), and t(14;20) are considered to have high‐risk myeloma. Patients with t(4;14) translocation are considered intermediate‐risk. All others are considered as standard‐risk.Risk‐adapted initial therapyStandard‐risk patients can be treated with lenalidomide plus low‐dose dexamethasone (Rd), or a bortezomib‐containing triplet such as bortezomib, cyclophosphamide, dexamethasone (VCD). Intermediate‐risk and high‐risk patients require a bortezomib‐based triplet regimen. In eligible patients, initial therapy is given for approximately 4 months followed by autologous stem cell transplantation (ASCT). Standard‐risk patients can opt for delayed ASCT if stem cells can be cryopreserved. In patients are not candidates for transplant, initial therapy is given for approximately 12–18 months.Maintenance therapyAfter initial therapy, lenalidomide maintenance is considered for standard‐risk patients who are not in very good partial response or better, while maintenance with a bortezomib‐based regimen should be considered in pateints with intermediate or high‐risk myeloma.Management of refractory diseasePatients with indolent relapse can be treated first with two‐drug or three‐drug combinations. Patients with more aggressive relapse often require therapy with a combination of multiple active agents. Am. J. Hematol. 88:225–235, 2013. © 2013 Wiley Periodicals, Inc.

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“…M onoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM), with a risk of progression of approximately 1% per year. [1][2][3] Monoclonal gammopathy of undetermined significance is defined by a serum monoclonal immunoglobulin level greater than 3 g/dL, less than 10% plasma cells in the bone marrow, and the absence of end-organ damage (hypercalcemia, renal insufficiency, anemia, and bone lesions, collectively referred to as CRAB symptoms) that can be attributed to the monoclonal plasma cell proliferative process. 4 Monoclonal gammopathy of undetermined significance is the most common plasma cell disorder.…”

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confidence: 99%

“…In a large population-based screening study conducted among Olmsted County, Minnesota, residents 50 years or older, MGUS was identified in 3.2%; age-adjusted prevalence rates were greater in men (4.0%) than in women (2.7%) and increased with age to 5.3% among persons 70 years or older and to 7.5% among residents 85 years or older. 2 Because MGUS is asymptomatic, only one-third of the MGUS patients detected by screening had been previously recognized through routine clinical care.…”

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Incidence of Monoclonal Gammopathy of Undetermined Significance and Estimation of Duration Before First Clinical Recognition

Therneau

Kyle

Melton

et al. 2012

Mayo Clinic Proceedings

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Objectives: To determine the incidence of monoclonal gammopathy of undetermined significance (MGUS) in the general population and to estimate the duration of occult MGUS before first diagnosis. Methods: To estimate incidence we used innovative methods to exploit the Olmsted County, Minnesota, MGUS prevalence data, along with follow-up from a large cohort of patients with clinically detected MGUS. The prevalence cohort consisted of 21,463 persons systematically screened for the presence or absence of MGUS. The clinical cohort consisted of 7472 patients with MGUS diagnosed at Mayo Clinic from January 1, 1990, to May 13, 2010. The incidence of MGUS was estimated using the prevalence estimates, the rate of MGUS progression, and the death rates from MGUS using Markov chain methods. Results: We estimate that the annual incidence of MGUS in men is 120 per 100,000 population at the age of 50 years and increases to 530 per 100,000 population at the age of 90 years. The rates for women are 60 per 100,000 population at the age of 50 years and 370 per 100,000 population at the age of 90 years. We estimate that 56% of women 70 years of age diagnosed as having MGUS have had the condition for more than 10 years, including 28% for more than 20 years. Corresponding values for men are 55% and 31%, respectively. At 60 years of age, the proportion of prevalent cases that are clinically recognized is 13%. This rate increases to 33% at the age of 80 years. Conclusion: In addition to an accumulation of cases, the age-related increase in prevalence of MGUS is related to a true increase in incidence with age. When first clinically recognized, MGUS has likely been present in an undetected state for a median duration of more than 10 years. M onoclonal gammopathy of undetermined significance (MGUS) is a precursor to multiple myeloma (MM), with a risk of progression of approximately 1% per year. [1][2][3] Monoclonal gammopathy of undetermined significance is defined by a serum monoclonal immunoglobulin level greater than 3 g/dL, less than 10% plasma cells in the bone marrow, and the absence of end-organ damage (hypercalcemia, renal insufficiency, anemia, and bone lesions, collectively referred to as CRAB symptoms) that can be attributed to the monoclonal plasma cell proliferative process. 4 Monoclonal gammopathy of undetermined significance is the most common plasma cell disorder. Indeed, almost 60% of patients presenting with a monoclonal gammopathy at Mayo Clinic have MGUS. In a large population-based screening study conducted among Olmsted County, Minnesota, residents 50 years or older, MGUS was identified in 3.2%; age-adjusted prevalence rates were greater in men (4.0%) than in women (2.7%) and increased with age to 5.3% among persons 70 years or older and to 7.5% among residents 85 years or older. 2 Because MGUS is asymptomatic, only one-third of the MGUS patients detected by screening had been previously recognized through routine clinical care.Although studies conducted so far provide data on the prevalence of MGUS and its re...

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Prevalence of Monoclonal Gammopathy of Undetermined Significance

Abstract: Among residents of Olmsted County, Minnesota, MGUS was found in 3.2 percent of persons 50 years of age or older and 5.3 percent of persons 70 years of age or older.

Cited by 1,129 publications

References 17 publications

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Amyloidogenicity and Clinical Phenotype Associated with Five Novel Mutations in Apolipoprotein A-I

Multiple myeloma: 2013 update on diagnosis, risk‐stratification, and management

Incidence of Monoclonal Gammopathy of Undetermined Significance and Estimation of Duration Before First Clinical Recognition

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