Final Report Summary - MGUS PROGNOSIS (Clinical studies on the precursor condition monoclonal gammopathy of undetermined significance - with focus on complications and prognosis)
The objectives of the projects were to analyse morbidity and mortality in detail among individuals with and without MGUS in the AGES-RS cohort. We have in collaboration with NCI performed electrophoresis and free-light chain analyses on all of the 5,764 individuals. This process took several months to perform and required detailed inspection of every individual and interpretation of the results. It turns out that 5.3% have MGUS and 0.6% light chain MGUS in the total population (table). After identifying indivuduals with and without MGUS, we performed cross linking to several registries to obtain nformation on the outcomes of interest, for example survival (from Registry of the total population), on disease (from patient Registry), on malignancies (from Cancer Registry) and on results obtained from the original AGES study. This step required detailed data cleaning and management, to prepare the data for statistical analyses.
Next step was performed mainly by two PhD-students that were focused on survival, thrombosis, malignant progression and obesity in MGUS. We have performed several analyses as described in the project proposal and we have presented these at international conferences. In addition to the ones which results are presented below we have also performed analyses to estimate the risk of cardiovascular disease, associations with diet and on bone disease. The main results were that individuals with MGUS have inferior survival compared to non-MGUS individuals examined the causes of death. Contrary to earlier reports we did not observe an association with obesity and MGUS, however we found obesity to increase the riskl of malignant progression. We have published a paper in JAMA Oncology where we showed that individuals with a known MGUS prior to myeloma diagnoses have a superior survival compared to myeloma patients without known MGUS.
Main results:
Prevalence of MGUS and LC-MGUS Methods:
We studied the screened, population-based, longitudinal cohort of the AGES Reykjavik Study, consisting of 5,764 elderly Icelandic men and women. Using blood samples from 2002-2006, participants were screened for MGUS using serum protein electrophoresis (SPEP) and free light chain (FLC) analysis. Results: Heavy chain MGUS was found through SPEP in samples from 300 participants (5.3%). A total of 118 participants (2.1%) had a normal SPEP but a pathological FLC ratio, and were initially classified as LC-MGUS. However, after reviewing the literature we propose a new definition of LC-MGUS, which involves a different FLC ratio cut-off, resulting in 33 LC-MGUS (0.6%) in our cohort. Status: Data collection and analysis finished. Abstract is ready. Manuscript submitted.
Project: Survival and causes of death in MGUS and LC-MGUS Methods: We used the population-based, longitudinal cohort of the AGES-Reykjavik Study, consisting of 5,764 elderly Icelandic men and women, where we in a previous study describe how we through screening found 300 individuals with MGUS (5.3%) and 33 individuals withLC-MGUS (0.6%). Information on outcome was supplemented by health care records. Survival was examined using a Cox proportional hazards model and Kaplan Meier analysis. Results: After a median follow-up time of 8 years, individuals with MGUS had a significantly higher risk of death (hazard ratio (HR) = 1.28 95% confidence interval (CI) 1.09-1.50) than individuals without MGUS, as did individuals with LC-MGUS (HR = 1.53 0.99-2.35). Individuals with MGUS and LC-MGUS had an increased risk of death from cancer (HR = 1.63 1.13-2.37) and from heart disease (HR = 1.60 1.15-2.21). Status: Manuscript ready for submission (after publication of manuscript I).
Project: Incidence of cardiovascular events in MGUS and LC-MGUS
Methods: Information on outcome was supplemented by health care records. Incidence of cardiovascular events was examined using a Cox proportional hazards model. Status: Analyses ongoing. Study IV: Risk of progression in MGUS and LC-MGUS. Methods: Information on outcome is supplemented by health care records. Incidence of lymphoproliferative disorders and risk factors for progression are examined using a Cox proportional hazards model. Status: Data collection finished. Analyses, interpretation of results, and manuscript writing ongoing
Project: Obesity and risk of MGUS
The aims of this study were to determine (i) if obesity is associated with an increased risk of MGUS and light-chain MGUS (LC-MGUS) and (ii) whether obesity is associated with a higher risk of progression to MM and other lymphoproliferative diseases. Data from the population based Age, Gene/Environment Susceptibility – Reykjavik Study (N=5,764) was used. We performed serum protein electrophoresis and serum free light-chain assay on all subjects to identify cases of MGUS and LC-MGUS. We included 12 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 mean follow-up of 7 years 18 had progressed to MM and 10 to other lymphoproliferative diseases (LP). We found no association between the 12 obesity markers and MGUS or LC-MGUS (odds ratios 0.99 to 1.02 for all 12 variables in both conditions). Based on a few number of cases, we found that high midlife BMI increased risk of progression to MM and other LP (HR=2.66 95% CI 1.17-6.05). To conclude, obesity was not a risk factor for MGUS or LC-MGUS. However, among individuals with MGUS/LC-MGUS, we found midlife overweight/obesity to be a risk factor for progression to MM and other LP.
Project: Diet and MGUS
Methods: Principal component analysis was used to extract dietary patterns and participants were ranked according to their adherence to each pattern extracted.
Results: A total of 575 (10.0%) MGUS cases were identified, of which 300 were heavy chain MGUS and 275 LC-MGUS. We used two dietary patterns in our analysis, an old traditional pattern and a healthy pattern, and found in a fully adjusted model that high adherence to the traditional pattern decreased risk of total MGUS (p trend = 0.004) and heavy chain MGUS (p trend = 0.022) and that high adherence to the healthy pattern decreased risk of LC-MGUS (p trend 0.022).
Conclusion: Our findings suggest that high adherence to the traditional Icelandic diet consumed during early and mid-19th century, including salted/smoked meat and fish, blood or liver sausage, rye bread, and milk decreases risk of MGUS later in life and high adherence to a pattern high in fruit and vegetables decreases risk of LC-MGUS. The mechanisms for these findings are unknown but our study indicates that food intake can alter the risk of developing MGUS.
We expect that the final results will give us valuable information on the impact of MGUS on overall health and survival, in addition to give information on potential risk factors for MGUS and myeloma development. Hopefully this can help us identify individuals at high risk of complication so that future health policies can focus on those individuals.
These findings have led us to start a nationwide screening study, which includes screening for MGUS in all Icelanders 40 years and older (iStopMM study (www.mgus.is)) which is a population-based screening study and already we have more than 50% of the total Icelandic population that have signed informed consent.
Next step was performed mainly by two PhD-students that were focused on survival, thrombosis, malignant progression and obesity in MGUS. We have performed several analyses as described in the project proposal and we have presented these at international conferences. In addition to the ones which results are presented below we have also performed analyses to estimate the risk of cardiovascular disease, associations with diet and on bone disease. The main results were that individuals with MGUS have inferior survival compared to non-MGUS individuals examined the causes of death. Contrary to earlier reports we did not observe an association with obesity and MGUS, however we found obesity to increase the riskl of malignant progression. We have published a paper in JAMA Oncology where we showed that individuals with a known MGUS prior to myeloma diagnoses have a superior survival compared to myeloma patients without known MGUS.
Main results:
Prevalence of MGUS and LC-MGUS Methods:
We studied the screened, population-based, longitudinal cohort of the AGES Reykjavik Study, consisting of 5,764 elderly Icelandic men and women. Using blood samples from 2002-2006, participants were screened for MGUS using serum protein electrophoresis (SPEP) and free light chain (FLC) analysis. Results: Heavy chain MGUS was found through SPEP in samples from 300 participants (5.3%). A total of 118 participants (2.1%) had a normal SPEP but a pathological FLC ratio, and were initially classified as LC-MGUS. However, after reviewing the literature we propose a new definition of LC-MGUS, which involves a different FLC ratio cut-off, resulting in 33 LC-MGUS (0.6%) in our cohort. Status: Data collection and analysis finished. Abstract is ready. Manuscript submitted.
Project: Survival and causes of death in MGUS and LC-MGUS Methods: We used the population-based, longitudinal cohort of the AGES-Reykjavik Study, consisting of 5,764 elderly Icelandic men and women, where we in a previous study describe how we through screening found 300 individuals with MGUS (5.3%) and 33 individuals withLC-MGUS (0.6%). Information on outcome was supplemented by health care records. Survival was examined using a Cox proportional hazards model and Kaplan Meier analysis. Results: After a median follow-up time of 8 years, individuals with MGUS had a significantly higher risk of death (hazard ratio (HR) = 1.28 95% confidence interval (CI) 1.09-1.50) than individuals without MGUS, as did individuals with LC-MGUS (HR = 1.53 0.99-2.35). Individuals with MGUS and LC-MGUS had an increased risk of death from cancer (HR = 1.63 1.13-2.37) and from heart disease (HR = 1.60 1.15-2.21). Status: Manuscript ready for submission (after publication of manuscript I).
Project: Incidence of cardiovascular events in MGUS and LC-MGUS
Methods: Information on outcome was supplemented by health care records. Incidence of cardiovascular events was examined using a Cox proportional hazards model. Status: Analyses ongoing. Study IV: Risk of progression in MGUS and LC-MGUS. Methods: Information on outcome is supplemented by health care records. Incidence of lymphoproliferative disorders and risk factors for progression are examined using a Cox proportional hazards model. Status: Data collection finished. Analyses, interpretation of results, and manuscript writing ongoing
Project: Obesity and risk of MGUS
The aims of this study were to determine (i) if obesity is associated with an increased risk of MGUS and light-chain MGUS (LC-MGUS) and (ii) whether obesity is associated with a higher risk of progression to MM and other lymphoproliferative diseases. Data from the population based Age, Gene/Environment Susceptibility – Reykjavik Study (N=5,764) was used. We performed serum protein electrophoresis and serum free light-chain assay on all subjects to identify cases of MGUS and LC-MGUS. We included 12 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 mean follow-up of 7 years 18 had progressed to MM and 10 to other lymphoproliferative diseases (LP). We found no association between the 12 obesity markers and MGUS or LC-MGUS (odds ratios 0.99 to 1.02 for all 12 variables in both conditions). Based on a few number of cases, we found that high midlife BMI increased risk of progression to MM and other LP (HR=2.66 95% CI 1.17-6.05). To conclude, obesity was not a risk factor for MGUS or LC-MGUS. However, among individuals with MGUS/LC-MGUS, we found midlife overweight/obesity to be a risk factor for progression to MM and other LP.
Project: Diet and MGUS
Methods: Principal component analysis was used to extract dietary patterns and participants were ranked according to their adherence to each pattern extracted.
Results: A total of 575 (10.0%) MGUS cases were identified, of which 300 were heavy chain MGUS and 275 LC-MGUS. We used two dietary patterns in our analysis, an old traditional pattern and a healthy pattern, and found in a fully adjusted model that high adherence to the traditional pattern decreased risk of total MGUS (p trend = 0.004) and heavy chain MGUS (p trend = 0.022) and that high adherence to the healthy pattern decreased risk of LC-MGUS (p trend 0.022).
Conclusion: Our findings suggest that high adherence to the traditional Icelandic diet consumed during early and mid-19th century, including salted/smoked meat and fish, blood or liver sausage, rye bread, and milk decreases risk of MGUS later in life and high adherence to a pattern high in fruit and vegetables decreases risk of LC-MGUS. The mechanisms for these findings are unknown but our study indicates that food intake can alter the risk of developing MGUS.
We expect that the final results will give us valuable information on the impact of MGUS on overall health and survival, in addition to give information on potential risk factors for MGUS and myeloma development. Hopefully this can help us identify individuals at high risk of complication so that future health policies can focus on those individuals.
These findings have led us to start a nationwide screening study, which includes screening for MGUS in all Icelanders 40 years and older (iStopMM study (www.mgus.is)) which is a population-based screening study and already we have more than 50% of the total Icelandic population that have signed informed consent.