21 research outputs found
Monoclonal gammopathy of undetermined significance : natural course and comorbidities
Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by an
overproduction of monoclonal immunoglobulins. MGUS is asymptomatic but clinically relevant since annually
0.5-1.5% of individuals with MGUS will develop multiple myeloma (MM) or another malignant
lymphoproliferative disease. Individuals with MGUS are followed for signs of progression, however, so far this
management strategy has never been evaluated. Results from previous studies have shown that individuals with
MGUS have inferior survival and increased risk of thrombosis compared to individuals without MGUS, yet all
studies to date have been performed on clinically established cohorts of MGUS patients, introducing a high risk
of selection bias. Recently, a new entity called light-chain MGUS (LC-MGUS) has been identified. Very little is
known about the epidemiology and clinical course of LC-MGUS.
In order to establish a clinically informative, correct, and easily applicable definition of LC-MGUS, and
describe the prevalence of MGUS and LC-MGUS in the population, we performed a large population-based
screening study. We screened more than 11,000 individuals from the Icelandic AGES-Reykjavik Study cohort
and the American PLCO Study cohort. The prevalence of MGUS was 4.8-5.2%. Based on findings from the two
cohorts and on statistical analysis of normal distributions, we propose a revised definition of LC-MGUS; (1) an
abnormal free light-chain ratio (1.65), (2) an elevated involved light chain concentration (40 mg/L or
higher), (3) no M-protein on serum protein electrophoresis or immunofixation, and (4) no evidence of end-organ
damage that can be attributed to a lymphoproliferative disorder. The prevalence of LC-MGUS in our study using
this definition was 0.9-1.0%. The prevalence of LC-MGUS increased with age (p<0.001), was higher in men
(p<0.001), and more common among blacks (2.9%) than whites (0.7%) or Asian/Pacific Islanders (0.2%). The
revised definition of LC-MGUS captures the condition in fewer but clinically relevant individuals.
We conducted three population-based studies with the purpose of studying the natural course and survival
of individuals with MGUS and LC-MGUS. We used the Icelandic AGES-Reykjavik Study cohort of 5,764
individuals, including 300 individuals with MGUS and 52 individuals with LC-MGUS, as well as a Swedish
cohort of 18,768 MGUS patients. Through the Swedish Cancer Register we identified all patients with MM
diagnosed from 1976 to 2013, as well as randomly sampled population-based controls. Individuals with MGUS
had a 1.2-fold (95% confidence interval (CI) 1.04-1.4) and individuals with LC-MGUS had a 1.6-fold (1.2-2.3)
increased risk of death compared to individuals without MGUS, during a median follow-up time of almost ten
years. The risk remained increased after progression to lymphoproliferative disease was taken into account. We
found a personal history of autoimmune disease to increase the risk of death significantly in both individuals
with MM (hazard ratio (HR) = 1.2, 1.2-1.3) and individuals with MGUS (HR = 1.4, 1.3-1.4). These findings
could be due to an underlying genetic susceptibility for both plasma cell disorders and other conditions, such as
autoimmune disease, or to the overproduction of light chains causing organ damage. We found that MM patients
with prior knowledge of MGUS had a better overall survival (median survival 2.8 years) than MM patients
without prior knowledge of MGUS (median survival 2.1 years). Among MM patients with a prior knowledge of
MGUS, a low M-protein concentration at MGUS diagnosis was predictive of worse survival in MM (HR = 1.9,
1.1-3.0), possibly due to patients with low M-protein concentration being followed less frequently. Our findings
support the recommendations of regular clinical follow-up of individuals with MGUS, regardless of M-protein
concentration.
In further analysis of the AGES-Reykjavik Study cohort, we assessed the causes of death and risk of
thrombosis among individuals with MGUS and LC-MGUS and found an increased risk of death from cancer
(HR = 1.8, 1.6-2.3) and from heart disease (HR = 1.4, 1.1-1.8), adjusted for age and sex. We found that a history
of thrombosis was more common in individuals with LC-MGUS (25%) than individuals with MGUS (10%) or
without MGUS (12%), and that individuals with LC-MGUS had an increased risk of a history of arterial
thrombosis especially (crude odds ratio (OR) = 2.5, 95% CI 1.3-4.9), compared to individuals without MGUS.
During a median follow-up time of almost nine years, we detected an almost two-fold risk of arterial thrombosis
in individuals with LC-MGUS compared to individuals without MGUS (crude HR = 1.9, 1.1-3.2). No increased
risk of venous thrombosis was detected in individuals with MGUS or LC-MGUS. Our results suggest that
previously detected increased risks of thrombosis in MGUS have been due to confounding factors. Our findings
on LC-MGUS point towards an elevated risk of arterial, but not venous, thrombosis.
In future investigations, we suggest attention is focused on characterizing the clinical, genetic, and
biochemical profiles of LC-MGUS, with the purpose of understanding the connection to cancer, to heart disease,
and to thrombosis
Incidence and risk factors for suicide and attempted suicide following a diagnosis of hematological malignancy.
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files.
This article is open access.Solid tumors are associated with an increased risk of suicide, however, there is limited detailed information on the risk of suicide in patients with hematological malignancies. Therefore, we conducted a population-based study including 47,220 patients with hematological malignancies (diagnosed 1992-2006) and their 235,868 matched controls to define the incidence and risk factors for suicide and suicide attempt. Information on suicides, suicide attempts, and preexisting psychiatric disorders was obtained from Swedish registers and individual medical records. There was a twofold increased (hazard ratio [HR] = 1.9, 95% confidence interval 1.5-2.3, P < 0.0001) risk of suicide/suicide attempt during the first 3 years after diagnosis in patients with hematological malignancies compared to matched controls. Of all hematological malignancies, multiple myeloma was associated with the highest risk (HR = 3.4; 2.3-5.0, P < 0.0001). Patients with a preexisting psychiatric disorder were at a very high risk of suicide and suicide attempt (HR = 23.3; 16.6-32.6, P < 0.0001), regardless of type of hematological malignancy. Among patients who committed suicide, 19% were in a palliative phase and 44% were in remission with no active treatment. In conclusion, the risk of suicide and suicide attempt is elevated in patients with hematological malignancies. Certain high-risk patients may benefit from early detection and preventive measures.Swedish Cancer Society
CAN 2012/483
regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet
20120004
Adolf H Lundin Charitable Foundation
Blodcancerfonde
History of autoimmune disease is associated with impaired survival in multiple myeloma and monoclonal gammopathy of undetermined significance: a population-based study
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesMultiple myeloma (MM) is a plasma cell disorder preceded by monoclonal gammopathy of undetermined significance (MGUS). Incidence of MM and MGUS is higher among patients with autoimmune disease. The aim of this study was to determine whether a history of autoimmunity has an impact on survival in MM and MGUS. Using high-quality national Swedish registries, we identified 8367 patients with MM, 18,768 patients with MGUS, and 110,251 matched control subjects, and obtained information on previous autoimmune disease in patients and controls. Cox regression was used to calculate hazard ratios (HRs) for overall survival with 95 % confidence intervals (CIs). In patients with MM and a prior autoimmune disease, the risk of death was significantly increased, HR = 1.2 (95 % CI 1.2-1.3) compared to MM patients with no history of autoimmunity. In MGUS patients, a prior autoimmune disease was associated with a significantly 1.4-fold elevated risk of death (95 % CI 1.3-1.4). When analyzing different types of autoimmune diseases, a history of ulcerative colitis had a stronger impact on survival in MM than in controls. Our findings that a history of autoimmune disease has a negative impact on survival in MM and MGUS could be due to shared underlying common genetic factors, or that patients with a history of autoimmunity develop more severe cases of MM and MGUS, or cumulative comorbidity in the individual. Our results suggest that more attention should be paid to comorbidity as a prognostic factor in MGUS and MM, and underlines the need for studies aimed at tailoring therapy according to comorbidity.Swedish Blodcancerfonden
Swedish Cancer Society
Stockholm County Council
Karolinska Institutet
Karolinska Institutet Foundations
University of Iceland
Icelandic Centre for Research (RANNIS)
Landspitali University Hospita
Obesity and risk of monoclonal gammopathy of undetermined significance and progression to multiple myeloma: a population-based study
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesAll multiple myeloma (MM) cases are preceded by the premalignant state monoclonal gammopathy of undetermined significance (MGUS). Results from previous studies show a positive association between obesity and MM; however, the association between obesity and MGUS is controversial. The aims were to determine (1) if obesity is associated with an increased risk of MGUS and light-chain MGUS (LC-MGUS) and (2) whether obesity is associated with a higher risk of progression to MM and other lymphoproliferative (LP) diseases. Data from the population-based Age, Gene/Environment Susceptibility-Reykjavik Study (N = 5764) were used. We performed serum protein electrophoresis and serum free light-chain assay on all subjects to identify MGUS and LC-MGUS cases. We included 11 different measures on current and previous obesity in our analysis. Logistic regression and Cox proportional-hazard regression were used to analyze the associations. A total of 300 (5.2%) MGUS and 275 (4.8%) LC-MGUS cases were identified. During a median follow-up of 8 years, 18 had progressed to MM and 11 to other LP diseases. We found no association between the 11 obesity markers and MGUS or LC-MGUS (odds ratios 0.81 to 1.15 for all 11 variables in both conditions). Interestingly, we found that high midlife body mass index increased risk of progression to MM and other LP diseases (hazard ratio, 2.66; 95% confidence interval, 1.17-6.05). To conclude, obesity was not associated with MGUS. However, we found overweight/obesity to be a risk factor for progression from MGUS to MM and other LP diseases, suggesting that obesity plays a role in the transformation of MGUS to MM.National Institutes of Health, National Institute on Aging
National Institute on Aging Intramural Research Program, a National Eye Institute Intramural Research Program Award
National Institute on Deafness and Other Communication Disorders, Division of Scientific Programs
Hjartavernd (the Icelandic Heart Association)
Althingi (the Icelandic Parliament)
University of Iceland Research Fund
Icelandic Centre for Research (RANNIS)
Landspitali University Hospital Research Fund
Karolinska Instituted Foundations
Marie Curie CIG
National Cancer Institute, National Institutes of Healt
Bone disease in monoclonal gammopathy of undetermined significance: results from a screened population-based study
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesPrevious studies have shown that individuals with monoclonal gammopathy of undetermined significance (MGUS) have an increased risk of fractures, although the underlying mechanisms remain unknown. Our aim was to analyze bone mineral density (BMD), bone volume, and risk of fractures among individuals with MGUS. We performed a screening using the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study cohort, consisting of 5764 elderly individuals, identifying 300 individuals with MGUS, and 275 with light-chain MGUS. Quantitative computerized tomography was performed in the lumbar spine and hip to evaluate BMD and bone geometry. Analysis of variance and the Tukey honest significance test were used to compare the groups. Hospital records were used to record fractures, with a mean follow-up of 6.9 years. Cox proportional hazard was used to compare fracture risk. No difference was found in BMD between subjects with MGUS and others in the spine (P = .34) or in total hip (P = .30). Individuals with MGUS had a significant increase in bone volume compared with others in the spine (P < .001) and total hip (P < .001). Overall, the risk of fractures was not significantly increased in individuals with MGUS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.94-1.50). Men with MGUS had a significantly increased fracture risk, compared with other men (HR, 1.46; 95% CI, 1.03-2.08). Our results show that although individuals with MGUS do not have decreased BMD, bone volume is increased, and MGUS men have a 50% increased fracture risk. These results indicate that bone disease and fractures in MGUS differ from processes known from osteoporosis.University of Iceland Research Fund
Icelandic Centre for Research (RANNIS)
Landspitali University Hospital Research Fund
Karolinska Institutet Foundations
Marie Curie Career Integration Grants (CIG)
National Institutes of Health, National Institute on Aging (NIA)
NIA Intramural Research Program
National Eye Institute
National Institute on Deafness and Other Communication Disorders Division of Scientific Programs, Hjartavernd
Althingi (the Icelandic Parliament)
National Cancer Institute Memorial Sloan Kettering Cancer Center
Icelandic National Bioethics Committe
Dietary intake is associated with risk of multiple myeloma and its precursor disease
Publisher's version (útgefin grein)The etiology of monoclonal gammopathy of undetermined significance (MGUS), the precursor state of multiple myeloma (MM), is mostly unknown and no studies have been conducted on the effect of diet on MGUS or progression from MGUS to MM. We aimed to explore the association between common foods and MGUS and progression to MM. Data from the population-based AGES Study (N = 5,764) were utilized. Food frequency questionnaire was used to assess dietary intake during adolescence, midlife, and late life. Serum protein electrophoresis and serum free light-chain assay was performed to identify MGUS (n = 300) and LC-MGUS cases (n = 275). We cross linked our data with the Icelandic Cancer Registry to find cases of MM in the study group. We found that intake of fruit at least three times per week during adolescence was associated with lower risk of MGUS when compared to lower fruit consumption (OR = 0.62, 95% CI 0.41–0.95). We additionally found that intake of fruit at least three times per week during the late life period was associated with decreased risk of progressing from MGUS to MM (HR = 0.34, 95% CI 0.13–0.89) when compared to lower intake. Adolescent intake of fruit may reduce risk of MGUS, whereas fruit intake after MGUS onset may reduce risk of progressing to MM. Our findings suggest that diet might alter the risk of developing MGUS and progression to MM.The AGES-Reykjavik Study was funded by NIH contract N01-AG-012100, the Intramural Research Program of the National Institute on Aging, by the Icelandic Heart Association, and the Icelandic Parliament. This work was supported by the Icelandic Centre for Research, RANNIS (S.Y. Kristinsson), the Landspitali University Hospital Research Fund (S.Y. Kristinsson), the Karolinska Instituted Foundations (S.Y. Kristinsson), the Marie Curie CIG (S.Y. Kristinsson), and the Memorial Sloan Kettering Core Grant (P30 CA008748) from the National Cancer Institute (O.Landgren). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer Reviewe
Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study
The associations between immune-related conditions and multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) have previously been investigated with inconsistent results. In a large population-based study, we identified 19 112 patients with MM, 5403 patients with MGUS, 96 617 matched control subjects, and 262 931 first-degree relatives. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MM and MGUS with immune-related conditions by use of logistic regression. A personal history of all infections combined was associated with a significantly increased risk of MM (OR = 1.2; 95% CI, 1.1-1.3), and a personal history of all conditions in the categories infections (OR = 1.6; 95% CI, 1.5-1.7), inflammatory conditions (OR = 1.4; 95% CI, 1.2-1.5), and autoimmune diseases (OR = 2.1; 95% CI, 1.9-2.4) was associated with a significantly increased risk of MGUS. Several specific immune-related conditions elevated the risk of MM and/or MGUS. A family history of autoimmune disease was associated with a significantly increased risk of MGUS (OR = 1.1; 95% CI, 1.00-1.2), but not MM. Our findings suggest that immune-related conditions and/or their treatment are of importance in the etiology of MGUS and possibly MM. The association of both personal and family history of autoimmune disease with MGUS indicates the potential for shared susceptibility for these conditions. (Blood. 2011; 118(24): 6284-6291
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Multiple Myeloma Patients With Prior Knowledge Of MGUS Have a Better Survival Compared To Multiple Myeloma Patients Without Prior Knowledge Of MGUS
Abstract
Background
A recent prospective cancer screening trial including over 77,000 individuals followed-up for over 10 years shows that multiple myeloma (MM) is consistently preceded by a precursor state, monoclonal gammopathy of undetermined significance (MGUS). Clinically, most newly diagnosed MM patients are unaware of their prior MGUS state. Importantly, among individuals diagnosed with MGUS, only a small proportion will develop MM or a related malignancy during their lifespan. Current clinical guidelines suggest lifelong, annual monitoring of individuals diagnosed with MGUSto detect progression to MM or related disorders. At this time, the impact of annual monitoring on the outcome of patients who eventually develop MM is unknown. In addition, as MGUS is usually diagnosed during work-up for another disorder, the impact of comorbidity in MM patients with prior knowledge of MGUS is unknown. We assessed the impact of prior knowledge of MGUS in relation to MM survival.
Patients and Methods
The study cohort consisted of 14,798 individuals diagnosed with MM in Sweden 1976-2005, with follow-up until 2007. A total of 394 patients had previously been diagnosed with MGUS. Patients diagnosed with MM were identified through the Swedish Cancer Register. MM patients with prior knowledge of MGUS were identified from a nationwide MGUS cohort which was established from in and out-patient units from major hospital-based hematology/oncology centers in Sweden. Details of sex, date of birth, date of diagnosis, type and concentration of M-protein at MGUS diagnosis, and comorbidities (autoimmune diseases, infections, other malignant diseases, ischemic heart diseases, heart failure, cerebrovascular diseases, chronic lung diseases and renal diseases) were gathered for all patients. Survival rate from time of MM diagnosis comparing patients with and without prior knowledge of MGUS was calculated with a Kaplan Meier method. Risk factors for death were analysed in a Cox proportional hazards model where relative risks (RR) and 95% confidence intervals (CIs) were calculated. A Chi-square test was used to evaluate whether there was a significant difference in comorbidities.
Results
MM patients with prior knowledge of MGUS had significantly (RR = 0.86; CI = 0.77-0.96) better survival (median = 2.8 years; 95% CI = 2.6-3.3) than MM patients without prior knowledge of MGUS (median = 2.1 years; 95% CI = 2.1-2.2; Figure). Older age at diagnosis (RR = 1.04; 95% CI = 1.04-1.05) was associated with an inferior survival, whereas female sex and recent year at diagnosis were related to improved survival: RR = 0.86 (CI = 0.83-0.89) and 0.95 (CI = 0.95-0.95), respectively. There was no difference in survival comparing MGUS patients with high (>1.5 g/dL) versus low (<1.5 g/dL) M-protein concentration (RR = 1.01; 95% CI 0.72-1.41). Unexpectedly, M-protein concentration ≤0.5 g/dL at MGUS diagnosis was associated with poored survival than M-protein concentration greater than 0.5 g/dL (RR = 1.86; 95% CI = 1.13-3.04, p=0.014).
Autoimmune diseases (p<0.001), infections (p<0.001), other malignant diseases (p<0.001), ischemic heart diseases (p<0.001), heart failure (p<0.001), cerebrovascular diseases (p<0.001), and renal diseases (p<0.001) at diagnosis of MM were significantly more common in MM patients with prior knowledge of MGUS than in MM patients without.
Conclusions
Based almost 15,000 MM patients diagnosed in Sweden between 1976 and 2005, for the first time, we found that prior knowledge of MGUS is associated with better survival (median overall survival 2.8 versus 2.1 years). Given patterns of co-morbidities, the observed survival difference is likely a reflection of the fact that MGUS patients are evaluated more often for signs of MM progression and may be diagnosed/treated at an earlier stage. The finding that low-risk MGUS patients that develop MM had a shorter survival rate is interesting and may be due to less intense monitoring and needs to be studied further. Our observations raise the question whether screening for MGUS, e.g., above the age of 50, could translate into earlier detection/treatment of MM (“early myeloma“) and lead to better survival. Future prospective studies are needed to explore these findings further.
Disclosures:
Turesson: Celgene Corp: Honoraria