Familial Aggregation of Multiple Myeloma and Its Precursor Monoclonal Gammopathy of Undetermined Significance (MGUS): A Population-Based Study in Sweden.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1678-1678
Author(s):  
Sigurdur Y Kristinsson ◽  
Magnus Bjorkholm ◽  
Lynn R. Goldin ◽  
Cecilie Blimark ◽  
Ulf-Henrik Mellqvist ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Hodgkin Lymphoma ◽  
Monoclonal Gammopathy ◽  
Familial Aggregation ◽  
Large Population ◽  
Population Based ◽  
Case Control ◽  
Population Based Study ◽  
First Degree Relatives ◽  
Undetermined Significance

Abstract Background: Evidence from multiply affected families, case-control and population-based registry studies implicate a role for genetic factors in multiple myeloma (MM). The aim of this large population-based familial case-control study was to quantify risks of MM, monoclonal gammopathy of undetermined significance (MGUS), and other lymphoproliferative disorders among first-degree relatives of MM patients. Methods: We identified 13,963 MM patients diagnosed in Swedish hospitals 1958–2005, with linkable relatives. Using the population-based central Population- and Multigenerational registries, we obtained 54,610 matched controls and first-degree relatives of MM patients (n=37,838) and controls (n=151,068). Relatives of MM patients and controls were linked with hospital-based outpatient registries and the central Swedish Cancer Registry to define occurrence of MGUS and lymphoproliferative malignancies. Measures of familial aggregation were calculated by a marginal survival model using relatives as the cohort. Results: First-degree relatives of MM patients had a significantly increased risk of developing MM [relative risk (RR)=2.1; (95% confidence interval (CI), 1.6–2.9)] and MGUS [2.1 (1.5–3.1)]. The risk estimates were very similar when we conducted analyses by gender of proband, by type of first-degree relative (parent, sibling, offspring), and by age at MM diagnosis (below/above 65 yrs) for probands. Among relatives of MM patients, we found no excess risk of chronic lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, or lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia. Conclusions: In this large population-based study, we found relatives of MM patients to have a 2-fold excess risk of developing MM and MGUS compared with relatives of controls. Our findings support the theory that there are common, shared susceptibility genes that predispose to MM and MGUS. Better characterization of early genetic lesions mediating monoclonal plasma-cell proliferation, survival, and migration in the bone marrow microenvironment will potentially provide clues to pathogenesis and allow identification of novel molecular targets.

scholarly journals Obesity and risk of monoclonal gammopathy of undetermined significance and progression to multiple myeloma: a population-based study

2017 ◽  
Vol 1 (24) ◽  
pp. 2186-2192 ◽  
Author(s):  
Marianna Thordardottir ◽  
Ebba K. Lindqvist ◽  
Sigrun H. Lund ◽  
Rene Costello ◽  
Debra Burton ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Multiple Myeloma ◽  
Body Mass ◽  
Monoclonal Gammopathy ◽  
High Body Mass Index ◽  
Population Based ◽  
Population Based Study ◽  
Increased Risk ◽  
Key Points ◽  
Undetermined Significance

Key PointsObesity is not associated with MGUS or LC-MGUS. High body mass index during midlife is associated with increased risk of progressing from MGUS and LC-MGUS to MM and other LP diseases.

scholarly journals Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 785-790 ◽  
Author(s):  
Celine M. Vachon ◽  
Robert A. Kyle ◽  
Terry M. Therneau ◽  
Barbara J. Foreman ◽  
Dirk R. Larson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Population Based ◽  
Detection Methods ◽  
Shared Environment ◽  
Serum Samples ◽  
Adjusted Risk ◽  
First Degree Relatives ◽  
Increased Risk ◽  
Undetermined Significance

Abstract We examined whether monoclonal gammopathy of undetermined significance (MGUS) is increased in first-degree relatives of multiple myeloma (MM) or MGUS patients. Probands were recruited from a population-based prevalence study (MGUS) and the Mayo Clinic (MM). Serum samples were collected from first-degree relatives older than 40 years and subjected to electrophoresis and immunofixation. The prevalence of MGUS in relatives was compared with population-based rates. Nine-hundred eleven relatives of 232 MM and 97 MGUS probands were studied. By electrophoresis, MGUS was detected in 55 (6%) relatives, and immunofixation identified 28 additional relatives for an age- and sex-adjusted prevalence of 8.1% (95% CI, 6.3 to 9.8). The prevalence of MGUS in relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, 21.0% for ages 40-49, 50-59, 60-69, 70-79, ≥ 80 years, respectively; P < .001). Using similar MGUS detection methods, there was a higher risk of MGUS in relatives (age-adjusted risk ratio [RR], 2.6; 95% CI, 1.9 to 3.4) compared with the reference population. The increased risk was seen among relatives of MM (RR, 2.0; 95% CI, 1.4 to 2.8) and MGUS probands (RR, 3.3; 95% CI, 2.1 to 4.8). The increased risk of MGUS in first-degree relatives of MGUS or MM patients implies shared environment and/or genetics.

scholarly journals Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 791-795 ◽  
Author(s):  
Ola Landgren ◽  
Sigurdur Y. Kristinsson ◽  
Lynn R. Goldin ◽  
Neil E. Caporaso ◽  
Cecilie Blimark ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Monoclonal Gammopathy ◽  
Case Reports ◽  
Population Based ◽  
Lymphocytic Leukemia ◽  
Degree Relative ◽  
First Degree Relatives ◽  
Non Hodgkin Lymphoma ◽  
Increased Risk ◽  
Undetermined Significance

Abstract Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.

scholarly journals Monoclonal gammopathy of undetermined significance and COVID-19: a population-based cohort study

2021 ◽  
Vol 11 (12) ◽  
Author(s):  
Saemundur Rognvaldsson ◽  
Elias Eythorsson ◽  
Sigrun Thorsteinsdottir ◽  
Brynjar Vidarsson ◽  
Pall Torfi Onundarson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cohort Study ◽  
Odds Ratio ◽  
Monoclonal Gammopathy ◽  
Large Population ◽  
Immune Dysfunction ◽  
Population Based ◽  
Study Group ◽  
Increased Risk ◽  
Undetermined Significance

AbstractMultiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81–1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52–1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19.

scholarly journals Parental longevity and survival among patients with multiple myeloma and monoclonal gammopathy of undetermined significance: a population‐based study

2019 ◽  
Vol 186 (1) ◽  
pp. 37-44
Author(s):  
Ingigerður S. Sverrisdóttir ◽  
Sigrún H. Lund ◽  
Ingemar Turesson ◽  
Magnus Björkholm ◽  
Lynn R. Goldin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Population Based ◽  
Population Based Study ◽  
Parental Longevity ◽  
Undetermined Significance

Increased Risk of Monoclonal Gammopathy in First-Degree Relatives of Patients with Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1672-1672
Author(s):  
Celine M Vachon ◽  
Robert Kyle ◽  
Terry Therneau ◽  
Dirk R Larson ◽  
Colin Colby ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Reference Population ◽  
Population Based ◽  
Protein Electrophoresis ◽  
Olmsted County ◽  
Serum Samples ◽  
First Degree Relatives ◽  
Increased Risk ◽  
Undetermined Significance

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a common pre-malignant plasma cell disorder associated with a 1% per year risk of progression to multiple myeloma or related malignancy. Since the risk factors for MGUS are poorly defined, the goal of the present study was to determine if the risk of MGUS is increased in first degree relatives of patients with known multiple myeloma (MM) or MGUS. Methods: MGUS probands (index cases) were recruited from a population-based prevalence study of MGUS in Olmsted County, MN while MM probands were recruited through the Mayo Clinic practice. Consenting probands were asked to provide contact information on all first-degree relatives ages 40 years and older. Serum samples were then collected from first-degree relatives with informed consent and subjected to agaraose-gel electrophoresis and immunofixation. The prevalence of MGUS in first-degree relatives of MM and MGUS probands was compared to population-based rates from Olmsted County using risk ratios (RR). For comparisons to the reference population, only cases detected by protein electrophoresis and confirmed by immunofixation were included so that the diagnostic strategy was identical in the two groups being compared. Results: Serum samples were obtained from 911 relatives of 329 unique families, including 493 siblings, 324 children and 94 parents of patients with MGUS or MM. Using protein electrophoresis, monoclonal protein was detected in the serum of 55 (6%) while immunofixation identified 28 additional relatives (3%), for an age- and sex-adjusted prevalence rate of 8.1% (95%CI: 6.3, 9.8). The age-specific prevalence of MGUS in first-degree relatives increased with age (1.9%, 6.9%, 11.6%, 14.6%, and 21.0% for ages 40–49, 50–59, 60–69, 70–79 and ≥80, respectively; P&lt;0.001). Based on similar MGUS detection methodology as the reference population, there was a significantly higher risk of MGUS in first-degree relatives (age-adjusted RR, 2.6, 95%CI: 1.9, 3.4) compared to the reference population. The increased risk (P&lt;0.001) was seen both in relatives of MM probands (RR, 2.0, 95%CI: 1.4, 2.8), as well as MGUS probands (RR, 3.3, 95%CI: 2.1, 4.8). This association was similar across age of proband, age and gender of relative, and relationship of the first-degree relative. When examining whether the increased risk of MGUS in relatives was specific to probands with a large monoclonal protein concentration or specific monoclonal immunoglobulin isotype (i.e. high-risk MGUS phenotype), there was suggestion of a greater risk for relatives of probands with a high (3 1.5 g/dL) M-protein (RR, 2.8, 95%CI: 2.0,3.8) compared to lower M-protein levels (RR, 1.8, 95%CI: 1.1,2.8) although the difference did not reach statistical significance (P=0.12). The risk of MGUS in relatives did not differ by proband’s isotype (IgG vs. other). Conclusions: First-degree relatives of patients with MM or MGUS have a greater than two-fold risk of MGUS compared to the general population, implying underlying genetic predisposition for these diseases and providing rationale for identifying genetic determinants of MGUS. This study also provides important baseline rates of MGUS in first-degree relatives that impact the clinical care of these patients.

scholarly journals Risk of Monoclonal Gammopathy of Undetermined Significance in First-Degree Relatives of Multiple Myeloma Cases By Cytogenetic Subtype

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4425-4425
Author(s):  
Alyssa I. Clay ◽  
Abdul Rishi ◽  
Shaji Kumar ◽  
S. Vincent Rajkumar ◽  
Alexandra J. Greenberg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Gammopathy ◽  
Research Funding ◽  
Familial Risk ◽  
Population Based ◽  
Olmsted County ◽  
First Degree Relatives ◽  
Increased Risk ◽  
Age And Sex ◽  
Undetermined Significance

Abstract We and others previously demonstrated an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of multiple myeloma (MM) and MGUS patients, underscoring a familial component to this disease. However, MM is known to be a collection of cytogenetically distinct diseases, with 40-50% of MM cases having a reciprocal translocation involving the IgH locus on chromosome 14q32 and in many of the remaining patients, trisomies. In a small proportion of cases, both IgH abnormalities and trisomies are found in the same clone. These MM cytogenetic subtypes are associated with differential prognosis. Whether there are differences in familial risk by cytogenetic subtypes is not known. Patients with MM were recruited from the Mayo Clinic Hematology practice in Rochester, Minnesota (MN) between 2005 and 2015. Serum samples were collected from first-degree relatives and subjected to electrophoresis and immunofixation for MGUS determination. Age- and sex-specific rates of MGUS from the population-based Olmsted County, MN, prevalence study were used as expected rates for the calculation of risk ratios (RRs) for comparisons of first-degree relatives. Cytogenetic subtypes were classified by FISH testing performed in the clinic and categorized into groups defined by IgH translocation , trisomy, intermediate/ high-risk disease (t(4;14), t(14;16), t(14;20), and del17p). Further, the distribution of cytogenetic subtypes was compared between MM cases with and without evidence of MGUS in first degree relatives using Chi square tests. Analyses were also subset to MM probands diagnosed in MN. There were a total of 442 MM probands, with 1235 first-degree relatives recruited and eligible for the study. MGUS was detected in 78 relatives, for an age- and sex-adjusted prevalence of 6.1% (4.7%-7.5%). Analyses comparing prevalence of MGUS in first degree relatives to population-based rates from Olmsted County showed a 2.5-fold (95% CI=1.9-3.0) increased prevalence. When performing analyses among MN probands only (RR=2.9; 95% CI=2.1-3.8), results were similar. Of the 442 probands, 310 had FISH performed on plasma cells (identified by cIG staining; cIg-FISH) at diagnosis. Of these cases, 49% had a trisomy, 23% had an IgH translocation, and 9% had both. Although the proportion of trisomies and IgH translocations were 4-6% higher among MM probands with a relative with MGUS compared to those without, these differences were not statistically significant (Table 1). MM probands with a first degree relative with MGUS also had a similar proportion of cytogenetic subtypes that are considered of intermediate or high risk compared to those MM without a family history (26.9% vs 25.2%) (p=0.79) (Table 1). When restricted to MM probands from MN, results remained non-statistically significant (Table 1). We showed an increased risk of MGUS in first-degree relatives of MM cases, implying shared environment and/or genetics underlying this malignancy. However, we did not find an association between family history of MGUS in MM probands and the cytogenetic subtypes examined. Larger cohorts are needed to examine if a relationship exists between cytogenetic subtypes of MM and familial risk. Disclosures Kumar: Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; Janssen: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding; BMS: Consultancy.

Increased Risks of Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Myelofibrosis (MF) among 24577 First-Degree Relatives of 11039 Patients with Chronic Myeloproliferative Disorders (MPD) in Sweden.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 680-680 ◽  
Author(s):  
Ola Landgren ◽  
Lynn R. Goldin ◽  
Sigurdur Y. Kristinsson ◽  
Jan Samuelsson ◽  
Magnus Bjorkholm
Keyword(s):  
Myeloid Leukemia ◽  
Familial Aggregation ◽  
Large Population ◽  
Case Series ◽  
Population Based ◽  
Local Hospital ◽  
Population Based Study ◽  
First Degree Relatives ◽  
Increased Risk ◽  
Familial Clustering

Abstract Background. Familial clustering of PV, ET, MF, and chronic myeloid leukemia (CML) has been reported through case reports and smaller case series. Recently, several studies reported that in families with multiple MPD patients, the JAK2 mutation is not an early germ line predisposing factor for MPD but rather a facilitator of proliferative advantages. However, the degree of familial clustering in the population has not been defined. We have conducted the first large population-based study to quantify risks of developing MPD and related malignancies in first-degree relatives of MPD patients. Methods. Using high-quality central population-based registries, we identified 6217 PV, 2838 ET, and 1984 MF patients diagnosed in Swedish hospitals 1958–2005 (Cancer and local hospital-based registries), with linkable relatives; 43550 frequency-matched controls (Population registry); and first-degree relatives of cases (n=24577) and controls (n=99542) (Multigenerational registry). Relatives of MPD patients and controls were linked with the Cancer and local hospital-based registries to define occurrence of MPD and other related neoplasms. We used a marginal survival model to calculate relative risks (RR) and 95% confidence intervals (CI) as measures of familial aggregation. Results. Compared with controls, relatives of MPD patients had significantly increased risks of PV (RR=5.70; 95% CI 3.55–9.14), ET (RR=7.37; 95% CI 3.67–14.81), and MF (RR=3.53; 95% CI 1.59–7.85). Risks were similar when we restricted the analyses to relatives of patients with the same MPD (PV-PV, ET-ET, and MF-MF) Also, risk-estimates were virtually the same for various types of first-degree relatives (parents, siblings, offspring); the same was true when we calculated risks by age at MPD of cases (above vs. below 65 yrs), and sex of relatives. Age at diagnosis of MPD was not different for case and control relatives. Furthermore, relatives of MPD patients (vs. controls) had a borderline increased risk of CML (RR=1.86; 95% CI 0.90–3.74; p=0.07). As expected, we found excess of subsequent acute myeloid leukemia (AML) (n=271; 2.5%) and myelodysplastic syndrome (MDS) (n=27; 0.2%) among MPD patients; however, there were no increased risks of AML or MDS among relatives of MPD patients. Conclusions. In this first large population-based study including more than 11000 MPD patients and their almost 25000 linkable first-degree relatives, we found 3- to 7-fold elevated risks of developing MPDs among first-degree relatives of MPD patients. Our results support the hypothesis that there are common, strong, shared susceptibility genes that predispose to PV, ET, MF, and possibly CML.

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