History of autoimmune disease is associated with impaired survival in multiple myeloma and monoclonal gammopathy of undetermined significance: a population-based study

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.

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

British Journal of Haematology ◽

10.1111/bjh.15883 ◽

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

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

Blood ◽

10.1182/blood.v112.11.1678.1678 ◽

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.

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Kristinsson SY, Pfeiffer RM, Björkholm M, et al. Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance and multiple myeloma: a population-based study. Blood. 2010;115(24):4991–4998.

Blood ◽

10.1182/blood-2011-01-329144 ◽

2011 ◽

Vol 117 (14) ◽

pp. 3938-3938

Keyword(s):

Multiple Myeloma ◽

Venous Thrombosis ◽

Monoclonal Gammopathy ◽

Population Based ◽

Population Based Study ◽

Undetermined Significance

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Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies

Blood Cancer Journal ◽

10.1038/s41408-021-00480-w ◽

2021 ◽

Vol 11 (5) ◽

Author(s):

Sæmundur Rögnvaldsson ◽

Thorvardur Jon Love ◽

Sigrun Thorsteinsdottir ◽

Elín Ruth Reed ◽

Jón Þórir Óskarsson ◽

...

Keyword(s):

Multiple Myeloma ◽

Early Treatment ◽

Monoclonal Gammopathy ◽

Controlled Trial ◽

Participation Rate ◽

Population Based ◽

Early Therapy ◽

Screening Study ◽

Undetermined Significance

AbstractMonoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.

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Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study

Blood ◽

10.1182/blood-2008-12-194241 ◽

2009 ◽

Vol 113 (22) ◽

pp. 5412-5417 ◽

Cited By ~ 579

Author(s):

Ola Landgren ◽

Robert A. Kyle ◽

Ruth M. Pfeiffer ◽

Jerry A. Katzmann ◽

Neil E. Caporaso ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Gammopathy ◽

Population Based ◽

Serum Samples ◽

M Proteins ◽

Cancer Screening Trial ◽

Risk Of Progression ◽

Study Population ◽

A Prospective Study ◽

Undetermined Significance

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma-cell proliferative disorder associated with a life-long risk of progression to multiple myeloma (MM). It is not known whether MM is always preceded by a premalignant asymptomatic MGUS stage. Among 77 469 healthy adults enrolled in the nationwide population-based prospective Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, we identified 71 subjects who developed MM during the course of the study in whom serially collected (up to 6) prediagnostic serum samples obtained 2 to 9.8 years prior to MM diagnosis were available. Using assays for monoclonal (M)–proteins (electrophoresis/immunofixation) and kappa-lambda free light chains (FLCs), we determined longitudinally the prevalence of MGUS and characterized patterns of monoclonal immunoglobulin abnormalities prior to MM diagnosis. MGUS was present in 100.0% (87.2%-100.0%), 98.3% (90.8%-100.0%), 97.9% (88.9%-100.0%), 94.6% (81.8%-99.3%), 100.0% (86.3%-100.0%), 93.3% (68.1%-99.8%), and 82.4% (56.6%-96.2%) at 2, 3, 4, 5, 6, 7, and 8+ years prior to MM diagnosis, respectively. In approximately half the study population, the M-protein concentration and involved FLC-ratio levels showed a yearly increase prior to MM diagnosis. In the present study, an asymptomatic MGUS stage consistently preceded MM. Novel molecular markers are needed to better predict progression to MM in patients with MGUS.

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Prevalence of Light-Chain Monoclonal Gammopathy of Undetermined Significance (LC-MGUS) among Olmsted County, Minnesota Residents Aged 50 Years or Greater.

Blood ◽

10.1182/blood.v108.11.5060.5060 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5060-5060

Author(s):

S. Vincent Rajkumar ◽

Robert Kyle ◽

Matthew Plevak ◽

Raynell Clark ◽

Dirk Larson ◽

...

Keyword(s):

Multiple Myeloma ◽

General Population ◽

Natural History ◽

Light Chain ◽

Monoclonal Gammopathy ◽

Olmsted County ◽

Serum Samples ◽

Geographic Population ◽

History Of ◽

Undetermined Significance

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant plasma cell disorder that carries a 1% per year risk of progression to multiple myeloma (MM) or related malignancy. The prevalence and natural history of MGUS, in which by definition intact immunoglobulin heavy chain (IgH) is expressed, has been well described. However, up to 20% of myeloma (MM) is characterized by complete lack of IgH expression (Light-chain MM); the prevalence of a corresponding precursor entity, light chain MGUS (LC-MGUS) has not been determined. We report the first prevalence estimates of LC-MGUS in the general population from a large, well-defined geographic population using modern laboratory techniques. Methods: The cohort for this study was derived from one previously assembled by us to estimate the prevalence of MGUS (N Engl J Med2006;354:1362-9). The original cohort used to estimate the prevalence of MGUS consisted of 21,463 of the 28,038 enumerated residents aged 50 or over of Olmsted County Minnesota as of January 1, 1995. The sensitive serum free light chain (FLC) assay (The Binding Site Limited, Birmingham, U.K.) was performed on stored serum samples from these 21,463 persons. IgH expression was determined by immunofixation on all FLC results that had an abnormal kappa/lambda ratio (<0.26 or >1.65). LC-MGUS was defined as the presence of an abnormal FLC ratio and a negative immunofixation for IgH expression. Results: Adequate stored serum samples were available in 20,733 (97%) of the 21,463 persons. To date, the FLC assay has been performed and results were available for analysis on samples from 16,637 persons. An abnormal FLC ratio was observed in 572 persons. IgH expression was detected in 255 of these cases on immunofixation; these persons are considered as having MGUS, and were excluded from the estimation of LC-MGUS prevalence. This resulted in 317 persons out of 16,637 who had an abnormal FLC ratio without evidence of IgH expression, resulting in an estimated prevalence of LC- MGUS of 2%. Of the 317 cases of LC-MGUS identified in this study, 217 were kappa and 100 were lambda; in 35 cases the presence of the corresponding monoclonal light chain was apparent on immunofixation. The median age of the cohort of LC-MGUS was 62 years; males=151, females =166. The involved FLC level ranged from 0.118–270.0 mg/dL. The FLC ratio ranged from 0.014–0.253 (lambda) and 1.67–511.01 (kappa). So far, progression to multiple myeloma has occurred in 4 patients, a rate much higher than what is expected based on the prevalence of myeloma in the general population. Two additional patients have developed CLL. Conclusions: LC-MGUS is prevalent in 2% of the general population aged 50 years of age or older. The natural history of this disorder needs to be determined.

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Peripheral neuropathy and monoclonal gammopathy of undetermined significance: A population-based study including 15,351 cases and 58,619 matched controls

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.09.541 ◽

2019 ◽

Vol 19 (10) ◽

pp. e329

Author(s):

Sæmundur Rögnvaldsson ◽

Vilhjálmur Steingrímsson ◽

Ingemar Turesson ◽

Magnus Björkholm ◽

C. Ola Landgren ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Monoclonal Gammopathy ◽

Population Based ◽

Population Based Study ◽

Undetermined Significance

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

Blood ◽

10.1182/blood-2008-12-192575 ◽

2009 ◽

Vol 114 (4) ◽

pp. 785-790 ◽

Cited By ~ 85

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.

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

Blood Cancer Journal ◽

10.1038/s41408-021-00580-7 ◽

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.

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