Prevalence Of Monoclonal Gammopathy Of Undetermined Significance Research Articles

High Incidence of Transient Monoclonal Gammopathies after Allogeneic Hematopoietic Stem Cell Transplantation in Non-Myeloma Patients

BackgroundThe clinical and biological relevance of a monoclonal gammopathy (MG) that newly arises after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in non-myeloma patients is unknown. In healthy subjects, the incidence of monoclonal gammopathy of undetermined significance (MGUS) ranges from 3-9% and significantly increases with age. In these individuals, the absolute risk of progression to plasma cell myeloma at 20 years is 5-58%, depending on the MGUS subtype. The aim of this study was to investigate the incidence, the course and the clinical relevance of post-allo-HSCT MG.MethodsWe retrospectively analyzed a cohort of 403 non-myeloma patients (median age: 48y, range: 18-69y, 57% men, 43% women) who underwent allo-HSCT at the Division of Hematology of the University Hospital Zurich between January 2004 and December 2014. In these patients, a serum electrophoresis and an immunofixation was performed every 3-6 months post allo-HSCT. Patients with a MGUS before allo-HSCT were excluded from the study. The immunoglobulin subtype and the light chain restriction of the MG were determined by immunofixation. The most frequent indications for allo-HSCT were acute leukemia (AL, n=305), chronic myeloid leukemia (CML, n=30), myelodysplastic syndrome (MDS, n=24), and myeloproliferative neoplasm (MPN, n=20).ResultsThe incidence of a MG after allo-HSCT (56/403 patients, 14%) was higher than the reported incidence of MGUS in age-matched healthy subjects (estimated prevalence of MGUS in 50y old men: 3.2%) and in contrast to healthy subjects did not correlate with age. The majority of patients carried a IgG paraprotein (80%), while IgM paraproteins were detected in 12.5% of patients. Rarely, two types of paraproteins were identified simultaneously in the same patient. In most patients (44/56, 79%), the MG appeared within the first year after allo-HSCT and was transient with a median duration of 5.8 months (range 2.5 - 43.9 months). However, in 7/56 (13%) patients, the MG persisted until the end of the observation period (median duration 33 months, range 12-45.6 months). Only one patient showed a very late (7y post allo-HSCT) but also transient appearance of a MG. Development of plasma cell myeloma was not observed in patients with post allo-HSCT MG. Conditioning regimen, GvHD, immunoglobulin treatment and cessation of immunosuppressive therapy did not predict the appearance of post allo-HSCT MG.ConclusionsOur study reveals a high incidence of a transient MG after allo-HSCT that is not related to age of the recipient and follows the expected immunoglobulin subtype distribution. Importantly, patients with post allo-HSCT were not at increased risk of developing plasma cell myeloma as observed for MGUS in otherwise healthy subjects inferring a distinct pathogenetic mechanism. The transient nature of MG early after allo-HSCT suggests an association with the immune reconstitution process and future studies will determine whether expansion of a specific plasma cell clone can occur during engraftment of donor-derived hematopoiesis. [Display omitted] DisclosuresTheocharides:Novartis: Consultancy, Honoraria.

The Incidence of Senile Cataract and Glaucoma is Increased in Patients with Plasma Cell Dyscrasias: Etiologic Implications.

Plasma cell dyscrasias, including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), Waldenström macroglobulinemia (WM) and light chain AL amyloidosis, are characterized by clonal expansion of plasma cells which produce a vast amount of an immunoglobulin-derived M-protein. We noted that MGUS diagnosis often coincided with diagnoses of senile cataract and glaucoma and tested the associations of MGUS, MM, WM and AL amyloidosis with subsequent eye diseases identified from the Swedish patient registers between 1997 and 2012. Standardized incidence ratios (SIRs) for senile cataract was significantly increased to 1.80 after MGUS, 1.70 after MM, 1.85 after WM and 2.31 after AL amyloidosis. The SIR for glaucoma was 1.60 after MGUS, 1.76 after WM and 2.18 after AL amyloidosis. All SIRs decreased systematically from age below 60 years to over 79 years, but most risks were also significant in age group over 79 years. The M-protein and the related increase in blood viscosity could be a novel etiologic discovery for these common eye diseases. As MGUS prevalence is around 3% at 60 years and close to 10% at age over 80 years, its contribution to the eye disease burden is expected to be remarkably high.

Increased Monoclonal Components: Prevalence in an Italian Population of 44 474 Outpatients Detected by Capillary Electrophoresis.

SummaryBackgroundIdentification, quantification and typing of M-Proteins (MP) play an important role in the diagnosis, classification and monitoring of monoclonal gammopathies both of malignant origin (eg. Multiple Myeloma) and of unknown origin. Previous evidence attests that MGUS (Monoclonal Gammopathy of Undetermined Significance) detected by agarose gel electrophoresis has a prevalence of 3.2% in the general population. Therefore, our study aimed to verify this data by means of capillary zone electrophoresis (CZE).MethodsCZE was performed to evaluate the prevalence of M-Protein (MP) in 44.474 consecutive outpatients of all ages with a prescription for serum protein electrophoresis over a 2-year period (2008 and 2009). All MPs that were identified were then typed by immunofixation electrophoresis on agarose gel (IFE).ResultsIn subjects aged over 50 (23.408, i.e., 52.6% of the whole cohort) MP ≤30 g/L (MGUS) was identified in 6.0% of cases, with a frequency nearly double than that previously reported. The population was then divided into ten-year age groups: the 71–80 age group had the highest percentage of MP (29%), followed by 61–70 (27%), 51–60 (18%), 81–90 (12%), 41–50 (8%), 31–40 (3%), >90 (2%) and <30 (1%). The frequency of MP types (IFE) was the same in each age group, with IgG Kappa being the most represented class.ConclusionsAccording to the high MGUS prevalence observed in this study, these results may be useful especially for general practitioners, because the identification even of small MP (analytical sensitivity: 0.5 g/L) may help optimize clinical management.

Agent Orange Exposure and Monoclonal Gammopathy of Undetermined Significance: An Operation Ranch Hand Veteran Cohort Study.

Multiple myeloma has been classified as exhibiting "limited or suggestive evidence" of an association with exposure to herbicides in Vietnam War veterans. Occupational studies have shown that other pesticides (ie, insecticides, herbicides, fungicides) are associated with excess risk of multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance (MGUS); however, to our knowledge, no studies have uncovered such an association in Vietnam War veterans. To examine the relationship between MGUS and exposure to Agent Orange, including its contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in Vietnam War veterans. This was a prospective cohort study conducted in 2013 to 2014, testing for MGUS in serum specimens collected and stored in 2002 by the Air Force Health Study (AFHS). The relevant exposure data collected by the AFHS was also used. We tested all specimens in 2013 without knowledge of the exposure status. The AFHS included former US Air Force personnel who participated in Operation Ranch Hand (Ranch Hand veterans) and other US Air Force personnel who had similar duties in Southeast Asia during the same time period (1962 to 1971) but were not involved in herbicide spray missions (comparison veterans). Agent Orange was used by the US Air Force personnel who conducted aerial spray missions of herbicides (Operation Ranch Hand) in Vietnam from 1962 to 1971. We included 479 Ranch Hand veterans and 479 comparison veterans who participated in the 2002 follow-up examination of AFHS. Agent Orange and TCDD. Serum TCDD levels were measured in 1987, 1992, 1997, and 2002. Risk of MGUS measured by prevalence, odds ratios (ORs), and 95% CIs. The 479 Ranch Hand veterans and 479 comparison veterans had similar demographic and lifestyle characteristics and medical histories. The crude prevalence of overall MGUS was 7.1% (34 of 479) in Ranch Hand veterans and 3.1% (15 of 479) in comparison veterans. This translated into a 2.4-fold increased risk for MGUS in Ranch Hand veterans than comparison veterans after adjusting for age, race, BMI in 2002, and the change in BMI between 2002 and the time of blood draw for TCDD measurement (adjusted OR, 2.37; 95% CI, 1.27-4.44; P=.007). Operation Ranch Hand veterans have a significantly increased risk of MGUS, supporting an association between Agent Orange exposure and multiple myeloma.

Clinical characteristics, outcomes and predictors of progression to multiple myeloma (MM) in 61 patients with solitary plasmacytoma

female gender (HR: 0.86; 95% CI: 0.75-0.97); and skeletal related events (HR: 0.77, 95% CI: 0.57-1.02). Conclusions: Older age, male gender, high comorbidity burden, anemia, and hypercalcemia were risk factors for death in the treated NDMM Medicare population. Additional analyses are warranted to understand the relationship between treatments and death. PO-172 Clinical prevalence of monoclonal gammopathy of undetermined significance (MGUS) in the United States: estimating the burden on health care R.S. Go, K. Swanson, L.R. Sangaralingham, E.B. Habermann, R.A. Kyle, N.D. Shah Division of Hematology; Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN; Optum Labs, Cambridge, MA Background: Current information on the prevalence of MGUS is mostly derived from serologic testing of population samples. The serologic prevalence is estimated to be 3,200 and 5,840 per 100,000 persons age >50 years for predominantly white and black populations, respectively (Kyle 2006, Landgren 2007). However, in practice, MGUS is almost always discovered only during the evaluation of symptomatic patients suspected of having lymphoplasmacytic cancers. Therefore, the serologic prevalence may overestimate the clinical prevalence of MGUS (Therneau 2012). Methods:We conducted a retrospective analysis of data from 20052014 using the Optum Labs Data Warehouse, a large database including administrative claims information on over 100 million privately insured and Medicare Advantage enrollees throughout the United States. We calculated the MGUS clinical prevalence and assessed trends over time according to year of diagnosis and demographic subgroups. We used the total number of adult (age >18 years) lives covered as the denominator. Prevalence rates were expressed as the number of existing cases per 100,000 enrollees. Changes in trend over time were evaluated using the CochranArmitage test. Results: In 2014, the overall clinical prevalence of MGUS was 100.0 per 100,000. The clinical prevalence differed significantly within demographic subgroups (P <0.001) including sex (male: 94.3, female: 105.4), age (18-29 years: 1.7; 30-39 years: 7.1; 40-49 years: 31.1; 50-59 years: 98.4; 60-69 years: 241.8; 70-79 years: 500.4; 80+ years: 693.4), as well as race and ethnicity (white: 123.5; black: 164.7; Asian: 49.1; Hispanic: 64.1; unknown/unavailable: 67.6). During the 10 year study period, there was a significant increase in the clinical prevalence over time for all patients (27.3 in 2005) and across all demographic subgroups (P <0.001; shown in part in the Figure). Conclusions: The clinical prevalence of MGUS in the US has significantly increased over the past decade, but remains at least 10 times lower than published serologic prevalence. Future public health studies in MGUS should take into account this difference when estimating the burden of medical care. PO-173 Clinical characteristics, outcomes and predictors of progression to multiple myeloma (MM) in 61 patients with solitary plasmacytoma E.E. Manasanch, C.M. Claussen, W. Dong, J. Shah, H. Lee, S. Thomas, V.K. Reed, B.S. Dabaja, S. Milgrom, C.C. Pinnix, S. Parmar, N. Shah, K. Patel, Q. Bashir, M. Qazilbash, R. Orlowski, L. Feng, D. Weber Dept of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas; Dept of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Dept of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; Dept of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas Solitary plasmacytoma (SP) is a malignancy in bone (BP) or extramedullary soft tissue (EP) at risk for progression to MM. We present preliminary characteristics, outcomes and predictors of progression to MM in a cohort of 61 patients (pt). We retrospectively searched our database for “plasmacytoma” from 1999 until 2014. 192 patients were identified. 131 patients were excluded due to incorrect diagnosis, lack of baseline data or pt duplication. Panel 1A shows baseline characteristics; median follow-up time was 5 years for censored observations. Definitive radiation was a component of therapy in 95% of patients. Median overall survival (OS) was 12.5 years for BP and not reached for EP (p1⁄40.89). Univariate cox hazard model showed larger tumor size and serum paraprotein (SePa) of 1g/dL at diagnosis was associated with worse OS (HR 1.16, p1⁄40.08 and HR 0.24 [for SePa < 1g/dL], p1⁄40.09, respectively). At 5 years, only 17% of EP pts vs. 39% of BP pts had progressed to myeloma (TTM) (p1⁄40.10) (Panel 1B). Univariate analysis of baseline characteristics for TTM identified higher serum calcium (HR 1.30) and location (head and neck versus long bones, 15th International Myeloma Workshop, September 23-26, 2015 e181

Chronic hepatitis C virus infection and lymphoproliferative disorders: mixed cryoglobulinemia syndrome, monoclonal gammopathy of undetermined significance, and B-cell non-Hodgkin lymphoma.

Chronic hepatitis C (CHC) has been associated with lymphoproliferative disorders (LPD) such as mixed cryoglobulinemia syndrome (MCS), monoclonal gammopathy of undetermined significance (MGUS), and B-cell non-Hodgkin lymphoma (B-NHL). The aim of the present study is to assess MCS, MGUS, and B-NHL prevalence in a cohort of CHC-infected patients and to evaluate the association of demographic, clinical, and virologic factors with the presence of LPDs. A total of 121 CHC patients with LPDs (50 M, 71 F; mean age 61.5 ± 11.8) and 130 CHC patients without extrahepatic manifestations (60 M, 70 F; mean age 60.4 ± 9.2) were retrospectively enrolled from a cohort of 1313 CHC patients between January 2006 and December 2013. Patients with LPDs included: 25 patients with MCS (9 M, 16 F; mean age 60.2 ± 1.4), 55 patients with MGUS (18 M, 37 F; mean age 61.3 ± 12.1), and 41 patients with B-NHL (23 M, 18F; mean age 62.5 ± 11.0) RESULTS: Patients with MCS (25/1313; 1.9%), MGUS (55/1313; 4.2%), and B-LNH (41/1313; 3.1%) did not differ in age, severity of liver disease, HCV genotype, and response to antiviral therapy. Using multivariate logistic regression analysis, a positive association was found between the presence of cirrhosis and MGUS (odds ratio [OR] = 2.8924, 95% confidence interval [CI] 1.2693-6.5909; P = 0.012) and between cirrhosis and B-NHL (OR = 3.9407, 95% CI 1.7226-9.0153; P = 0.001), whereas no association with MCS diagnosis emerged. Despite the pathogenetic mechanism of HCV-associated LPDs is still unclear, cirrhosis is an additional risk factor for the development of lymphoproliferative disorders in patients with chronic HCV infection.

Prevalence of monoclonal gammopathy in HIV patients in 2014.

IntroductionIn non-HIV patients, Monoclonal Gammopathy of Undetermined Significance (MGUS) is associated with an increased risk of subsequent development of haematologic malignancies, especially multiple myeloma (MM) and it has been recently demonstrated that MM is always preceded by a MGUS phase. A higher prevalence of MGUS and MM has been observed in HIV patients compared to the general population. Nevertheless, it has been shown that MGUS in the context of HIV can disappear with antiretroviral therapy (ART). So, measuring MGUS prevalence in HIV patients in the recent period appears of special interest.Materials and MethodsFrom January to June 2014, in each out-patient seen in our unit, a serum protein electrophoresis was performed.ResultsA total of 393 patients were screened. Eight patients with HIV2 and one patient with HIV1+HIV2 infection were excluded. Finally, 383 patients (173 female, 210 male) with HIV1 infection were analyzed. Characteristics of patients were as follows: median age 42.2 years (19.1–79.1), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) co-infection 47 (18.8%), median CD4 610 (2–1758), CD8 793 (113–4010), presence of a past AIDS event for 88 patients (23%). Median time with HIV infection was 11 years (0–30). Three hundred fifty-nine patients (93.7%) were on ART for a median duration of 105 months (0–287). For 320 patients (83.6%), viral load was below 50 viral copies/ml. Twelve cases of MGUS (3.1%) were observed: IgG Kappa (five cases), IgG Lambda (five cases), biclonal with two IgG Kappa (one case) and in one case, three monoclonal immunoglobulins were observed (IgG Kappa×2+IgG Lambda). The monoclonal immunoglobulin's level was low and below 1 g/l in all cases except two (2.1 and 11.6 g/l). No factor was found to be predictive of the presence of MGUS in particular age, CD4, HBV/HCV co-infection, viral load or ART.ConclusionsIn the context of modern ART, the prevalence of MGUS remains above those observed in the general population. Even if the level of monoclonal spike observed in our cohort is generally low, an excess risk of subsequent development of MM could be present. Nevertheless, a prospective follow-up of HIV patients with MGUS is necessary to determine this risk.

Unveiling skeletal fragility in patients diagnosed with MGUS: no longer a condition of undetermined significance?

Monoclonal gammopathy of undetermined significance (MGUS) is a common finding in clinical practice, affecting greater than 3% of adults aged 50 years and older. As originally described, the term MGUS reflected the inherent clinical uncertainty of distinguishing patients with a benign stable monoclonal plasma cell disorder from subjects destined to progress to malignancy. There is now clear epidemiologic evidence, however, that patients with MGUS suffer from a significantly increased fracture risk and that the prevalence of MGUS is increased in patients with osteoporosis. Despite this relationship, no clinical care guidelines exist for the routine evaluation or treatment of the skeletal health of patients with MGUS. Recent work has demonstrated that circulating levels of at least two cytokines (CCL3/MIP-1α and DKK1) with well-recognized roles in bone disease in the related monoclonal gammopathy multiple myeloma are also increased in patients with MGUS. Further, recent imaging studies using high-resolution peripheral quantitative CT have documented that patients with MGUS have substantial skeletal microarchitectural deterioration and deficits in biomechanical bone strength that likely underlie the increased skeletal fragility in these patients. Accordingly, this Perspective provides evidence that the "undetermined significance" portion of the MGUS acronym may be best replaced in favor of the term "monoclonal gammopathy of skeletal significance" (MGSS) in order to more accurately reflect the enhanced skeletal risks inherent in this condition.

Immunoglobulin G subclass analysis in psoriatic arthritis.

The occurrence of monoclonal gammopathy of undetermined significance (MGUS) is common in chronic immune mediated disorders. This increased monoclonal antibody production could result from chronic stimulation of lymphocytes, with the immunoglobulin G (IgG) subtype accounting for the majority of cases in psoriatic arthritis (PsA). We aimed to identify IgG subclass profiles in patients with PsA and to determine association with specific disease characteristics. Serum samples from 221 patients with PsA from a single cohort were analyzed for their serum IgG subclass levels. All patients fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria and were followed at 6-month to 12-month intervals according to a standard protocol. MGUS was defined as the occurrence of a discrete band in the gammaglobulin region on at least 2 separate serum protein electrophoresis tests performed 6 months apart. Patients with high abnormal IgG subclass levels were compared to patients with normal levels using descriptive tests. Elevations of IgG1-4 were common in PsA, with ∼20%-49% of patients having elevations of each subclass, IgG2 being the most common subclass abnormality. However, no clinical-serological correlation was found in the group with abnormal IgG2 levels. Of the 38 patients with MGUS, elevations in IgG1 were most common. Patients with an abnormal IgG1 subclass level were more likely to have a discrete band in the gammaglobulin region, higher prevalence of MGUS, and abnormal erythrocyte sedimentation rate or C-reactive protein levels. Determination of the IgG subclass concentration in PsA did not seem to add any significant value in identifying specific disease manifestations. However, this study provides insight into the pathological process leading to MGUS in PsA.

Racial disparities in the prevalence of monoclonal gammopathies: a population-based study of 12 482 persons from the National Health and Nutritional Examination Survey

Multiple myeloma (MM) incidence is markedly higher in blacks compared with whites, which may be related to a higher prevalence of monoclonal gammopathy of undetermined significance (MGUS). Our objective was to define the prevalence and risk factors of MGUS in a large cohort representative of the US population. Stored serum samples from the National Health and Nutritional Examination Survey (NHANES) III or NHANES 1999-2004 were available for 12,482 individuals of age ⩾50 years (2331 'blacks', 2475 Hispanics, 7051 'whites' and 625 'others') on which agarose-gel electrophoresis, serum protein immunofixation, serum-free light-chain assay and M-protein typing were performed. MGUS was identified in 365 participants (2.4%). Adjusted prevalence of MGUS was significantly higher (P<0.001) in blacks (3.7%) compared with whites (2.3%) (P=0.001) or Hispanics (1.8%), as were characteristics that posed a greater risk of progression to MM. The adjusted prevalence of MGUS was 3.1% and 2.1% for the North/Midwest versus South/West regions of the United States, respectively (P=0.052). MGUS is significantly more common in blacks, and more often has features associated with higher risk of progression to MM. A strong geographic disparity in the prevalence of MGUS between the North/Midwest versus the South/West regions of the United States was found, which has etiologic implications.

Association between the delta estimated glomerular filtration rate and the prevalence of monoclonal gammopathy of undetermined significance in Korean males.

Background. We investigated the association between the reduction in the estimated glomerular filtration rate (eGFR) and the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in Korean males. Methods. We enrolled 723 healthy Korean males. Serum creatinine concentration, serum electrophoresis, serum immunofixation, and the serum free light chain assay were performed. We calculated delta eGFR per year (ΔeGFR/yr). The prevalence of MGUS was compared based on the ΔeGFR/yr and age group. Results. Thirteen (1.8%) of 723 participants exhibited the monoclonal band on serum immunofixation. Prevalence of MGUS by age group was 0.00% (0/172 for 40 years), 1.63% (6/367 for 60 years), and 3.80% (7/184 for >60 years). The median decrease in ΔeGFR/yr was 5.3%. The prevalence of MGUS in participants in their 50s with >5.3% decline in ΔeGFR/yr was significantly higher than those with <5.3% decrease in ΔeGFR/yr (3.16% versus 0.00%; P = 0.049). The prevalence of MGUS in participants in their 50s with >5.3% decrease in ΔeGFR/yr was similar to that of healthy males in their 60s. Conclusion. Using the rate of reduction in ΔeGFR/yr in healthy Korean males who had their serum creatinine level checked regularly may increase the MGUS detection rate in clinical practice.

Prevalence of Monoclonal Gammopathy of Undetermined Significance in Asia: A Viewpoint From Nagasaki Atomic Bomb Survivors

Exposure to ionizing radiation is a known environmental risk factor for a variety of cancers including hematological malignancies, such as leukemia, myelodysplastic syndromes, and multiple myeloma. Therefore, for Hiroshima and Nagasaki atomic bomb survivors (surviving victims who were exposed to ionizing radiation emitted from the nuclear weapons), several cancer-screening tests have been provided annually, with government support, to detect the early stage of malignancies. An M-protein screening test has been used to detect multiple myeloma at an early stage among atomic bomb survivors. In the screening process, a number of patients with monoclonal gammopathy of undetermined significance (MGUS), in addition to multiple myeloma, have been identified. In 2009 and 2011, we reported the age- and sex-specific prevalence of MGUS between 1988 and 2004 and the possible role of radiation exposure in the development of MGUS using the screening data of more than 1000 patients with MGUS among approximately 52,000 Nagasaki atomic bomb survivors. The findings included: (1) a significant lower overall prevalence (2.1%) than that observed in Caucasian or African-origin populations; (2) a significantly higher prevalence in men than in women; (3) an age-related increase in the prevalence; (4) a significantly higher prevalence in people exposed to higher radiation doses only among those exposed at age 20 years or younger; and (5) a lower frequency of immunoglobulin M MGUS in Japanese patients than in patients in Western countries. The large study of MGUS among Nagasaki atomic bomb survivors has provided important findings for the etiology of MGUS, including a possible role of radiation exposure on the cause of MGUS and an ethnicity-related difference in the characteristics of MGUS.

Five years' Follow-Up Study For Frequency Of Monoclonal Gammopathy Of Undetermined Significance (MGUS) In a Korean Elderly Urban Cohort

BackgroundThe prevalence of monoclonal gammopathy of undetermined significance (MGUS) increases with patient age and varies by race. However, reliable data on the epidemiology of MGUS is limited in Korea. We previously reported the prevalence of MGUS among 1000 participants of a Korean Elderly Urban Cohort recruited from 2005 to 2006 (First Wave, Park HK Am J Hematol. 2011;86:752-5); age and gender-adjusted prevalence of MGUS was estimated as 3.3% (95% confidence interval [CI] = 2.0-4.6%). Here, we report the five years' follow-up study for frequency of MGUS between 2010 and 2011. MethodsKorean Longitudinal Study on Health and Aging (KLoSHA) is a population-based, prospective cohort study of health, aging, and common geriatric diseases in a population aged ≥ 65 years in Seongnam-si, a satellite city of Seoul. Of the random sample of 1118 candidates from 61,730 Korean elderly individuals, 698 respondents agreed to participate in baseline KLoSHA study between 2005 and 2006. A total of 680 with available samples were screened for MGUS. We followed them and collected their serum between 2010 and 2011 (Second Wave). The screening of MGUS in the Second Wave was performed using serum protein electrophoresis followed by immunofixation assays; MGUS was defined by the presence of a serum monoclonal protein (M-protein), at a concentration <3 g/dL, and in the absence of end organ damage. Bone marrow study was not performed unless the patient was suspicious of multiple myeloma. To validate complete follow-up data, information regarding vital status was obtained from the National Population Registry of Korea National Statistical Office by using a unique resident registration number. Overall survival was calculated from the date of First wave to death from any cause. ResultsOf the 680 respondents (21 with MGUS, 659 without MGUS) in the First Wave, 361 (53%) agreed to participate in the Second Wave. Causes of nonattendance were death in 20%, refusal in 19%, move to other area in 6%, and loss to contact in 3%. Of the 361 respondents, 10 were identified to have MGUS. Overall frequency of MGUS is 2.8% (95% CI: 1.3 - 5.0%). Among 21 patients with MGUS in the First Wave, 9 were followed up in the Second Wave. Six of them showed persistent MGUS. One of them showed mild anemia with persistent M-protein of 1.4g/dL suggestive of progression to multiple myeloma, but was not confirmed because of early death just after screening. Interestingly, M-protein was disappeared in remaining 2 patients with MGUS in the First wave. Among 659 respondents without MGUS in the First Wave, 352 were followed up in the Second Wave. Four of them were newly diagnosed with MGUS. In Kaplan-Meier survival analysis, there was no significant difference of survival between respondents with MGUS and without MGUS in the First Wave (P = 0.66 by Log-rank test). ConclusionFive years' follow-up data showed the natural clinical course of MGUS. The diagnosis of MGUS was not associated with an increased risk of death in Korean elderly population. The interesting finding was that M-protein was disappeared in some patients with MGUS. High rate of non-attendance (47%) in Second Wave is the major limitation. Disclosures:No relevant conflicts of interest to declare.

Development Of Solid Malignancies In Patients With Monoclonal Gammopathy Of Undetermined Significance (MGUS): A Population-Based Study Of 17,315 Patients

BackgroundWhile patients with monoclonal gammopathy of undetermined significance (MGUS) are known to be at an increased risk of developing multiple myeloma, Waldenström macroglobulinemia, and primary amyloidosis, the risk of developing non-hematologic malignancies is less clear. A recent report suggested that MGUS patients have a 1.56-fold increased risk of developing nonhematologic malignancies. An excess risk of developing nonmelanoma skin (RR = 2.04), endocrine (RR = 3.34), breast (RR = 1.32), kidney and urinary tract (1.58), respiratory (RR = 1.42), male reproductive system (RR = 1.32), and GI cancers (RR = 1.25) has been reported for people with MGUS (Blood Oct 13 2011;118(15):4086-4092). This study constructed a cohort by discovering MGUS status through medical workup. Therefore, associations discovered might be related to the reason the test was performed more than the result of the test. This study aimed to determine if there was an increased risk of solid malignancies in persons with MGUS using a large, population-based, systematically screened cohort. MethodsThe population-based cohort established to estimate the prevalence of MGUS was examined for this study (N Engl J Med 2006; 354:1362-1369). Of the 28,038 residents of Olmsted County, Minnesota age 50 years or older as of January 1, 1995, 21,463 individuals' serum samples were collected. All samples were evaluated with serum electrophoresis and immunofixation to determine MGUS status. The Mayo Clinic Medical Index from 1/1/1975 to last follow up or 5/31/2006 was used to link MGUS status to other diagnoses. All patients diagnosed with a solid malignancy were identified, and disease prevalence was determined for cases and controls. For MGUS patients who progressed to MM or related disorder, only solid malignancy diagnoses made prior to progression was considered. A second analysis was performed in which only malignancies that developed after the MGUS screening or diagnosis date were considered. Results17,315 patients with 435,021 person-years of follow-up were included in the study. Any patient who was blinded in the initial cohort could not be included. Patients with MGUS (n=605) had a mean follow up of 24.64 years (range 0.11 to 30.57) while controls (n=16,710) had a mean of 25.14 years (range 0.01 to 31.40) of follow up. The risk ratio for developing any solid tumor was 1.08 (95% CI 0.94 to 1.25). Persons with MGUS had a 1.61-fold increased risk of developing respiratory tumors over controls. MGUS patients did not have a significantly increased risk of developing cancer in any other anatomical position studied, including bone, brain, breast, endocrine, eye, gastrointestinal, kidney, skin (melanoma or non-melanoma), oral/nasal/pharyngeal, reproductive, or salivary gland. MGUS patients were not found to be at increased risk of developing tumors with a specific pathology over controls. The second analysis, which considered only tumors that developed after the MGUS screening or diagnosis date, showed that MGUS patients were not at an increased risk of respiratory tumors (RR 1.28, p=0.21). According to this analysis, MGUS patients are at decreased risk of developing non-melanoma skin cancer (RR 0.76, p=0.003). No statistically significant increased risk of any solid tumor was identified through this analysis. ConclusionThis study used a systematically screened population-based cohort to determine if patients with MGUS are at an increased risk of developing solid tumors. The analysis suggests that patients with MGUS have a significantly increased risk of developing respiratory malignancies (RR 1.61, p=0.01). However, when only tumors diagnosed after MGUS screening or diagnosis date were considered, this risk was no longer significant (RR 1.28, p=0.21). Contrary to previous reports, we did not find patients with MGUS to be at an increased risk of developing other solid malignancies. The discrepancy between these findings and previously reported increased risk may be related to the elimination of ascertainment bias in this population-based cohort universally screened for the presence or absence of MGUS. Accurately understanding the risks associated with MGUS, a condition affecting 3% percent of the population over 50 years of age, may allow for more informed recommendations for screening and counseling for these patients. Disclosures:Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

SAT0208 Prevalence of Monoclonal Gammopathy of Undetermined Significance (MGUS) in Systemic Sclerosis: Report from Two Italian Centers

BackgroundMonoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant clonal plasma cell disorder. It is defined by the presence of serum levels of a monoclonal paraprotein lower than 3...

Immunoparesis and monoclonal gammopathy of undetermined significance are disassociated in advanced age

Immunoparesis and a skewed serum free light chain (FLC) ratio are indicators of immune dysfunction predictive of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). Previous studies have reported increased prevalence of MGUS by age, but no study has examined the relationship between immunoparesis and abnormal FLC ratios in the elderly. We screened 453 older adults (median age, 80 years; range, 65-96) to characterize the patterns of immunoparesis and abnormal FLC ratio in relation to MGUS. We defined MGUS in 4.4% of the subjects; the prevalence was 12.5% among individuals of >90 years. In MGUS (vs. non-MGUS) cases, immunoparesis and abnormal FLC ratios were detected in 70.0% (vs. 49.0%; P = 0.07) and 50.0% (vs. 12.9%; P = 0.0001), respectively. Based on small numbers, MGUS patients with abnormal FLC ratio were borderline (P = 0.07) more likely to have immunoparesis. Overall, the prevalence of immunoparesis varied in a nonlinear fashion, with lowest frequencies in the youngest and oldest groups. Our observed disassociation between MGUS prevalence and impaired immunoglobulin production suggests that separate mechanisms are involved in the development of MGUS and immunoparesis in advanced age. These findings emphasize the need for molecularly defined methods to characterize myeloma precursor states and better predict progression to MM.

Five-Years' Follow-up Study for Frequency of Monoclonal Gammopathy of Undetermined Significance (MGUS) in a Korean Elderly Urban Cohort

AbstractAbstract 5007We previously reported the prevalence of MGUS in a Korean Elderly Urban Cohort recruited from 2005 to 2006 (First Wave, Park HK Am J Hematol. 2011;86:752–5). Their plasma samples were screened using immunofixation and free light chain (FLC) assays. Age and gender-adjusted prevalence rates of MGUS were estimated as 3. 3% (95% CI=2. 0–4. 6%), and the age-adjusted prevalence of MGUS was 4. 3% in men (95% CI=1. 9–6. 6%) and 2. 6% in women (95% CI=1. 0–4. 2%). And then we followed them and collected their serum between 2010 and 2011(Second Wave). Among 1, 000 participants of First Wave, 497 participated to the Second Wave and 419 agreed with the donation of serum for protein electrophoresis, immunofixation and FLC assays. Causes of nonattendance were death in 200 (40%), refusal in 197 (40%), move to other area in 69 (14%), and impossible contact in 37 (7%). The frequency of MGUS in Second Wave was 3. 10% (95% CI=1. 44–4. 76%) in all, 4. 27% (95% CI=1. 54–6. 99%) in men, and 1. 92% (95% CI=0. 06–3. 79%) in women. Among 35 MGUS patients in First Wave, 11 were followed. Eight of 11 had persistent MGUS and other 2 showed the disappearance of M protein in Second Wave. The last one showed mild anemia with persistent M protein of 1. 4g/dL suggestive of progression to MM, but was not confirmed because of early death just after Second Wave. Additional 4 MGUS newly developed in Second Wave among 408 persons without MGUS at First Wave. The mean amount of M protein in 13 patients with MGUS was 0. 55g/dL (range: 0. 2∼1. 4). Subtypes of M protein were predominantly A and G in 8 and 5 patients. Light chain was lambda, kappa and none in 8, 4, and 1 patient. Abnormal ratio of FLC was correlated with the presence of MGUS (p=0. 000). In conclusions, the frequency of MGUS is persistently lower in elderly Koreans (3. 1%) than other races. Disclosures:No relevant conflicts of interest to declare.

Development of Myelodysplastic Syndrome and Acute Leukemias in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS): A Population-Based Study of 17,315 Patients

AbstractAbstract ▪934▪This icon denotes a clinically relevant abstract Background:An increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) has been observed for over 40 years in patients with multiple myeloma (MM). While treatment for MM has been implicated as the cause of excess MDS/AML, the risk may also be related to the underlying plasma cell proliferative disease process or an inherent predisposition to other hematologic malignancies in patients with plasma cell disorders. A recent study found an increased risk of AML/MDS for patients with monoclonal gammopathy of undetermined significance (MGUS) where there is no confounding chemotherapy effect to consider (Mailankody S, Blood2011; 118:4086-92). However, that report is subject to detection bias (i.e. association is related to reason for electrophoretic testing rather than the result of the test) since the population was not uniformly screened for MGUS. The purpose of this study was to determine if there was an increased risk of AML/MDS and other acute leukemias in persons with MGUS in a large population-based cohort systematically screened for the presence or absence of MGUS. Methods:The study utilized the population-based cohort established to estimate the prevalence of MGUS in the general population (N Engl J Med 2006; 354:1362-9). Serum samples were collected from 21,463 of the 28,038 residents of Olmsted County, Minnesota age 50 years or older as of 1/1/1995. Serum electrophoresis and immunofixation were used to determine MGUS status by testing all serum samples for the presence of a monoclonal protein. MGUS status was then linked to diagnoses entered in the Mayo Clinic Medical Index from 1/1/1975 to last follow up or 5/31/2006. For any patient in whom the diagnosis of AML/MDS or acute lymphoblastic leukemia (ALL) was in doubt, the diagnosis was verified by medical record review. For MGUS patients who progressed to MM or related disorder, only diagnosis of leukemia made prior to progression was considered. Results:17,315 patients who consented to serum analysis were included in this study; blinded patients included in the original cohort could not be evaluated. The final study cohort represents 435,021 person-years of follow-up. Mean follow up for patients with MGUS (n=605) was 24.64 years (range 0.11–30.57); controls (n=16,710) had a mean follow up of 25.14 years (range 0.01–31.40). MGUS patients had a significantly higher risk of developing acute leukemia (AML/ALL) or MDS compared to controls, risk ratio 2.20 (95% CI 1.23–3.92), p=0.008 (see Table). There was a higher risk of developing AML/MDS compared to controls, risk ratio 1.80 (95% CI .09-3.59), p=0.09. The risk of developing MDS was statistically significant (RR=2.10, p=0.049). MGUS patients had a 4.18-fold increased risk of developing ALL (p=0.010) and a 2.35-fold increased risk of developing any acute leukemia (p=0.050) over the general population. In subset analysis, patients with IgA/IgG MGUS had a 1.99-fold increased risk of developing MDS (p=0.108), while patients with an IgM M spike had a 2.81-fold increased risk of developing MDS over controls (p=0.152). Though MDS was observed in patients with IgA, IgG, and IgM M-spikes, AML was only observed only in patients with IgA or IgG isotypes (n=2/484). Conclusion:Our population-based study suggests MGUS is associated with a 1.8-fold increased risk of developing MDS/AML over the general population. The risk of AML/MDS is more modest than the 8-fold increased risk suggested in a previous report (Mailankody S, Blood2011; 118:4086-92). The smaller risk ratios in our study are likely related to our population-based cohort design that uniformly screened for the presence or absence of MGUS, and thereby minimized any amplification of risk that can occur in the presence of ascertainment bias. We also found a significant increase in the risk of ALL in persons with MGUS that requires further study. Our study supports the hypothesis that there may be an inherent increased risk of acute leukemia and MDS in patients with plasma cell disorders that is independent of myeloma therapy.Table 1Association with MDS and Acute Leukemia, MGUS Patients versus ControlsOutcomeMGUSControlsRisk Ratiop valueCasesRate*CasesRate*MDS80.42710.202.100.049AML21.36371.111.230.779AML or MDS91.03990.571.800.094ALL41.43200.344.180.010Acute Leukemia62.43551.042.350.050Acute Leukemia or MDS131.571170.712.200.008*Rate per 100,000 person-years, age- and sex-adjusted Disclosures:No relevant conflicts of interest to declare.

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

ObjectivesTo 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. MethodsTo 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. ResultsWe 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. ConclusionIn 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.

Prevalence and type of monoclonal gammopathy of undetermined significance in an apparently healthy Nigerian population: a cross sectional study

BackgroundThe prevalence of monoclonal gammopathy of undetermined significance (MGUS), a premalignant plasma-cell disorder has not been determined in our geographic area Nigeria.MethodsA cross sectional survey was carried on apparently healthy Nigerians selected by multistage sampling technique from the cosmopolitan city of Lagos, Nigeria. Subjects enrolled into the study had 2-step screening for the presence, type and concentration of monoclonal band. Agarose-gel electrophoresis was performed on all serum samples, and any serum sample with a discrete band of monoclonal protein or thought to have a localized band was subjected to Immunofixation. Subjects were also evaluated for Bence jones proteinuria, haematological and biochemical parameters.ResultsFour hundred and ten subjects with a mean age of 45.68 ± 10.3 years, a median of 45.00 years and a range of 20 to 80 years were enrolled into the study. MGUS was identified in only one (0.24 percent) of the 410 study subject. This subject was demonstrated to have a double monoclonal gammopathy; IgGλ at 16.9 g/L and IgAκ at 8.5 g/L. None of them including the sole subject with MGUS had a monoclonal urinary light chain.ConclusionAmong residents of Lagos, Nigeria, MGUS was found in only 0.24% percent of apparently normal persons with a median age of 45 years. This suggests that MGUS which represents the earliest stage of monoclonal plasma/lymphoid cell proliferation is not a common finding in the relatively young population of Nigeria. Future epidemiologic studies dealing with plasma cell disorders in older people are required to carefully examine the relationship between environmental factors and prevalence of MGUS and its ultimate progression to MM.