ALBERT

Description: Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma (MM) and other lymphoproliferative disorders. Patients with MM have an increased risk of venous and arterial thrombosis. Results from previous studies have also shown an increased risk of thrombosis in MGUS. However, these studies have been performed on clinically established cohorts, and no previous study has examined the risk of thrombosis in light chain MGUS (LC-MGUS). Methods We performed a population-based study on the longitudinal cohort of the AGES-Reykjavik Study, consisting of 5,764 elderly Icelandic men and women. Through screening all participants with free light chain analysis and serum protein electrophoresis, MGUS and LC-MGUS were identified in 299 and 52 individuals, respectively. The outcome was first incidence/occurrence of venous or arterial thrombosis, as diagnosis or as cause of death. Information on outcomes was supplemented by health care records, available from nine years prior to study baseline and for a median follow-up time of 8.8 years. Through logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate history of arterial and venous thrombosis, respectively, at study baseline. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% CIs for the risk of first incidence of thrombosis during follow-up. Results A history of any thrombosis during the nine years prior to diagnosis was present in 30 (10.0%) of individuals with MGUS, 13 (25.0%) of individuals with LC-MGUS, and 643 (12.0%) of individuals without MGUS. In a model adjusting for age, sex, smoking, serum cholesterol levels, diabetes, hypertension, and family history of thrombosis, the odds of having had a thrombosis was not significantly different for neither MGUS (OR = 0.75, 95% CI 0.50-1.12) nor LC-MGUS (OR = 1.81, 0.92-3.58), compared to those without MGUS. During a median follow-up time of 8.8 years, 80 (26.8%) of individuals with MGUS, 14 (26.9%) of individuals with LC-MGUS, and 1,344 (25.0%) of individuals without MGUS were diagnosed with thrombosis. Individuals with MGUS and with LC-MGUS had no increased risk of arterial thrombosis, when adjusted for age, sex, cholesterol, diabetes, hypertension, smoking, and family history of thrombosis (HR 1.04, 0.82-1.32). Similarly, no increased risk was found in MGUS or LC-MGUS for venous thrombosis, in a model adjusted for age, sex, body mass index, and previous or current cancer (HR 0.89, 0.41-1.89). Excluding individuals with a diagnosis of thrombosis occurring before baseline, or adjusting for a personal history of thrombosis, did not affect the results. Summary and conclusions In this large, population-based, screening cohort study, we found no increased risk of arterial or venous thrombosis in MGUS. A history of thrombosis was more common in individuals with LC-MGUS, which might be an effect of higher age in LC-MGUS individuals. To our knowledge, this is the first study to investigate risk of thrombosis in LC-MGUS. The results from our screened study contradict previous findings from clinically established cohorts. Future work is needed to better understand observed differences between studies and across populations. For example, potential underlying factors may include aggregation of underlying comorbidities in clinically diagnosed MGUS patients, and biological variations (shared germline genetic susceptibility) by ethnic groups. Table. Risk of thrombosis in individuals with MGUS and LC-MGUS, compared to individuals without MGUS. MGUS LC-MGUS No MGUS No. HR (95% CI) No. HR (95% CI) No. HR (95% CI) Any thrombosis* 80 (26.76%) 1.01 (0.80-1.26) 14 (26.92%) 1.13 (0.80-1.26) 1,344 (25.02%) 1.00 (Reference) Arterial thrombosis† 76 (25.42%) 1.04 (0.82-1.32) 14 (26.92%) 1.16 (0.67-2.01) 1,240 (23.08%) 1.00 (Reference) Venous thrombosis†† 7 (2.34%) 0.89 (0.41-1.89) 0 (0.0%) - 151 (2.81%) 1.00 (Reference) *Results adjusted for age and sex. † Results adjusted for age, sex, smoking, hypertension, cholesterol, diabetes, and family history of arterial thrombosis. †† Results adjusted for age, sex, body mass index, and previous or current cancer. MGUS: monoclonal gammopathy of undetermined significance, LC-MGUS: light-chain monoclonal gammopathy of undetermined significance. HR: hazard ratio, CI: confidence interval. Disclosures Landgren: Celgene: Consultancy; BMJ Publishing: Consultancy; Onyx: Research Funding; International Myeloma Foundation: Research Funding; Bristol-Myers Squibb: Consultancy; Onyx: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; BMJ Publishing: Honoraria; Onyx: Consultancy; Medscape: Consultancy.

Description: Background Nearly all multiple myelomas (MM) are preceded by the premalignant state, monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic condition that needs no treatment. The etiology of MGUS and MM is to a large extent unknown. Two studies on the association between obesity and MGUS have been conducted with conflicting results, despite a reported association between obesity and MM. The aim of this study was to determine if obesity is associated with an increased risk of MGUS and light-chain MGUS (LC-MGUS) in a population-based screened cohort of individuals above the age of 65 years using extensive number of markers for current and early life obesity. Methods This study was based on participants from the Age, Gene/Environment Susceptibility – Reykjavik Study (AGES-RS), which is a continuation of the Reykjavik Study, a population-based study performed by the Icelandic Heart Association. In 1967, the Reykjavik Study began recruiting a sample of over 30,000 residents of Reykjavik from the 1907-1935 birth cohorts. In 2002, the AGES-RS began recruiting 5,764 of the surviving members. Serum protein electrophoresis (SPEP) and serum free light-chain assay were performed on all subjects. Obesity measures were performed at baseline, and participants were additionally asked about their weight at the age of 25 years. The measures at baseline included were weight (kg), body mass index (BMI) (kg/m2), percent body fat, fat (kg), and fat-free mass (kg) from bioimpedance, total body fat area (cm2), visceral and subcutaneous fat area (cm2), and waist circumference (cm). The association with MGUS and LC-MGUS was analyzed using logistic regression and adjustment was made for age and sex. Cox proportional-hazard regression was performed to test whether obesity was a risk factor for progression from MGUS to MM and lymphoproliferative diseases. Results A total of 304 (5.3%) MGUS cases and 118 participants (2.1%) with LC-MGUS were identified. No association was found between any of the obesity markers and MGUS (Table). A statistically significant positive association was found between obesity (BMI ≥ 30 kg/m2) at study baseline and LC-MGUS (Table). Weak but statistically significant association was found between LC-MGUS and BMI at baseline, weight, max weight, percent body fat, fat in kg, fat-free mass, and waist circumference (Table). No association was found on risk of MGUS using joint effect of early adulthood BMI and BMI at study entry. Analysis on the effect of the obesity markers on the progression from MGUS to MM and lymphoproliferative diseases showed no association. Conclusion In this large population-based cross-sectional study aimed at evaluating the association between obesity and MGUS and LC-MGUS, we found obesity (BMI ≥ 30 kg/m2) to be associated with 2-fold excess risk for LC-MGUS. An association was additionally found between several of the obesity markers used and LC-MGUS. Future studies are needed to clarify underlying mechanisms for this finding. However, we did not find an association between any of the obesity markers and MGUS. Taken together, we were unable to confirm the previously reported association between MGUS and obesity. Abstract 5706. Table: Obesity and risk of MGUS or light-chain MGUS (LC-MGUS) No MGUS MGUS LC-MGUS No MGUS vs. MGUS OR* (95%CI) No MGUS vs. LC MGUS OR* (95%CI) BMI (n)

Description: Background: All multiple myeloma (MM) cases are preceded by the premalignant state, monoclonal gammopathy of undetermined significance (MGUS). The etiology of MM and MGUS is to a large extent unknown. Few studies on the effect of diet on MM have been conducted and the results have been inconclusive. No studies have been conducted on the effect of diet on MGUS. Studying dietary patterns offers broader view of food consumption and possible effects of diet on diseases since many nutrients and other substances in foods act together. The aim of this study was to identify different dietary patterns at three time points throughout the lifespan and examine whether adherence to these patterns was associated with risk of MGUS and light chain MGUS (LC-MGUS) and progression to MM and other lymphoproliferative diseases. Methods: This study was based on participants from the AGES-Reykjavik Study (N=5,764; mean age 77 years). Participants gave information on frequency of intake of common foods from early life (14-19 years old), midlife (45-55 years old), and currently at study baseline (67 years and older). All participants were screened for MGUS and LC-MGUS by serum protein electrophoresis and serum free light-chain assay. We identified MM and other lymphoproliferative diseases by cross linking with the Icelandic Cancer Registry. Principal component analysis was used to extract dietary patterns. This method is data driven and forms new linear factors, (dietary patterns) by reducing data dimension and grouping correlated variables (food intake). For each pattern extracted a new variable is created, ranking participants on their adherence to that particular pattern. We used logistic regression to test association between adherence to the early life and midlife dietary patterns and MGUS and LC-MGUS, and Cox proportional hazard regression to test association between adherence to the late life patterns and progression to MM and other lymphoproliferative diseases. Results: A total of 300 (5.2%) MGUS cases and 52 (0.9%) LC-MGUS cases were identified. During 11 years of follow-up 18 cases had progressed to MM and 10 to other lymphoproliferative diseases. We extracted four dietary patterns from early life, four from midlife, and six from baseline. When analyzing MGUS and LC-MGUS cases combined we found that high adherence to pattern I from early life, the old traditional Icelandic diet (high intake of salted/smoked meat and fish, blood and liver sausage, rye bread, milk, oatmeal, and potatoes), decreased the risk (odds ratio (OR) = 0.89, 95% confidence interval (CI) 0.79-1.00), however no association was found when analyzing MGUS and LC-MGUS separately (Table 1). When analyzing midlife patterns we found that the estimate for pattern I, the old traditional Icelandic diet (high intake of salted/smoked meat and fish, blood and liver sausage, fish in salad or on bread, and meat meals) was similar to the findings from early life, although it did not reach a statistical significance (OR = 0.90, 95% CI 0.80 - 1.02). High adherence to pattern III (high intake of potatoes, whole wheat bread, milk, rye bread, and fish) from midlife decreased the risk of combined MGUS (OR = 0.88, 95% CI 0.79-0.98). When analyzing MGUS and LC-MGUS separately we found that high adherence to pattern III decreased the risk of LC-MGUS (OR = 0.69, 95% CI 0.53-0.90) but not MGUS. We did not find an association between the six patterns from late life and progression to MM. However when analyzing progression to MM and other lymphoproliferative diseases combined we found that high adherence to pattern VI (high intake of meat and milk, low intake of fish) increased the risk of progression (HR = 1.82, 95% CI 1.24-2.67). Further results can be seen in Table 1. Conclusion: Our findings suggest that high adherence to the old traditional Icelandic diet consumed during early and mid 19th century, including salted or smoked meat and fish, blood or liver sausage, rye bread, and potatoes decreases the risk of MGUS/LC-MGUS later in life. They additionally suggest an increased risk of progression to MM and other lymphoproliferative diseases, with high adherence to a pattern with high meat and low fish intake. The mechanisms for these findings are unknown but our study suggests that food intake can alter the risk of developing MGUS/LC-MGUS as well as the risk of progression to MM. Disclosures Korde: Medscape: Honoraria. Landgren:Medscape Myeloma Program: Honoraria; BMS: Honoraria; Takeda: Honoraria; Merck: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Description: Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma and other lymphoproliferative disorders. In individuals with MGUS, the average risk of progression to a lymphoproliferative disorder has been estimated to be 1% per year, however, most previous studies have been performed on clinically established cohorts and very few have been population-based. A high monoclonal (M)-protein concentration, non-isotype IgG, and skewed free light chain (FLC) ratio are routinely taken into account when assessing risk for progression. Other risk factors have also been identified, such as low serum albumin. Methods The cohort under study consisted of 299 individuals, 158 men and 141 women, with MGUS, identified through screening the participants of the population-based, longitudinal AGES-Reykjavik Study using serum protein electrophoresis and FLC assessment. The median age was 78 years (range 67-93 years). The outcome was first incidence of lymphoproliferative disorder, denoting multiple myeloma, lymphoma, amyloidosis, lymphocytic leukemia, plasmacytoma, and Waldenström's macroglubulinemia. Information on outcomes was supplemented by cross-linkage to national registries, and median follow-up time was 8.8 years. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of lymphoproliferative disorders. Results were adjusted for serum albumin in categories (below 35 g/L, 35-40 g/L, or above 40 g/L), M-protein concentration (above or below 15 g/L), FLC ratio, levels of free light chains, use of statins, smoking status, renal function in categories, and M-protein isotype. The multivariate model was reduced in a step-wise manner to a final model with only significant covariates. Results During follow-up, 26 of 299 individuals with MGUS proceeded to develop a lymphoproliferative disorder, representing a cumulative risk of 8.7% and an annual risk of 1.0%. MM occurred in 17 of 218 individuals with non-IgM MGUS, representing a cumulative risk of 7.8% and an annual risk of 0.9%. In multivariate analysis, the final model contained serum albumin, M-protein concentration, and isotype A versus all other isotypes. Low serum albumin (HR = 6.3, 95% CI 1.0-40.6 for

Description: Background Multiple myeloma (MM) and its precursor state monoclonal gammopathy of undetermined significance (MGUS) are two plasma cell dyscrasias whose etiology is largely unknown. Autoimmune disorders (AI) include a variety of conditions, and a history of AI has been found to increase the risk of several malignancies. A personal history of AI is associated with a significantly increased risk of MGUS and to some extent MM. History of AI is a predictor of poor survival in the general population. Aims The aim of the study was to determine whether a personal history of AI has an impact on survival in MM and MGUS. Methods Using national Swedish registries we identified 2,719 patients with MM, diagnosed between January 1, 2000, and December 31, 2006, and 4,276 patients with MGUS, diagnosed between January 1, 1988, and December 31, 2006, as well as 28,063 matched control subjects. Through the Swedish Inpatient Registry and Cause of Death Registry, we obtained information on previous AI and on survival, respectively, in patients and controls. We calculated hazard ratios (HR) and 95% confidence intervals (CI). We used the Kaplan-Meier method with log-rank test and Cox proportional hazards model to compare outcome among patients and controls with and without AI. We performed sub-group analyses on seven specific AI conditions; rheumatoid arthritis, pernicious anemia, chronic rheumatic heart disease, ulcerative colitis, polymyalgia rheumatica, giant cell arteritis, and psoriasis. We also performed analyses by M-protein concentration and M-protein isotype (MGUS only). Results A history of AI was found in 232 MM patients (9%) and in 822 MM controls (8%). Compared to controls with no history of AI, male and female controls with a history of AI had a significantly 2.1-fold increased (95% CI 1.7-2.4, and 95% CI 1.7-2.5, respectively) risk of dying (Figure 1). In patients with MM and a prior history of AI, compared to MM patients with no history of AI, the risk of dying was significantly increased in females (HR=1.5, 95% CI 1.2-2.0) and in males (HR=1.3, 95% CI 1.0-1.7). The increased risk of dying after a prior AI was greater in MM patients than in controls for the specific AI conditions rheumatoid arthritis (HR=1.8, 95% CI 1.2-2.5 for controls, HR=1.9, 95% CI 1.3-2.9 for MM patients) and giant cell arteritis (HR=1.9, 95% CI 1.1-3.5 for controls, HR=4.1, 95% CI 1.3-12.7 for MM patients). For the other specific conditions analyzed, the increased risk of dying after a prior AI was smaller in MM patients than in controls. A history of AI was found in 570 MGUS patients (13%) and in 1,312 MGUS controls (8%). Compared to controls with no history of AI, male and female controls with a history of AI had a 1.8-fold (95% CI 1.7-2.1) and a 2.4-fold (95% CI 2.2-2.7) increased risk of dying, respectively (Figure 2). In patients with MGUS and a prior history of AI, compared to MGUS patients with no history of AI, the risk of dying was significantly increased in males (HR=1.3, 95% CI 1.1-1.6) and in females (HR=1.9, 95% CI 1.6-2.3). The increased risk of dying after a prior AI was greater in MGUS patients than in controls for the specific AI condition ulcerative colitis (HR= 1.2, 95% CI 0.6-2.5 for controls, HR=2.6, 95% CI 1.4-5.1 for MGUS patients). For the other specific conditions analyzed, the increased risk of dying after a prior AI was smaller in MGUS patients than in controls. In patients with MGUS, the effect of a history of AI on survival was not statistically different by isotype (IgA, IgG, or IgM), or by M-protein concentration (above/below 2.0 g/dl) at MGUS diagnosis. Conclusions In this large, population-based study aimed at evaluating the influence of a history of AI on survival in MM and in MGUS, we found AI to be a risk factor for survival in both conditions. However, a prior AI was a stronger predictor of survival in individuals without MM or MGUS. For certain AI conditions a history of AI had a greater impact on survival in MM or MGUS patients than in the general population. More attention should be paid to comorbidity as a prognostic factor in MM, and to the need for tailoring therapy according to comorbidity. Disclosures: No relevant conflicts of interest to declare.

Description: 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 (

Description: 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.