Risk Of Monoclonal Gammopathy Of Undetermined Significance Research Articles

A Brazilian Rare-Disease Center's Experience with Glucosylsphingosine (lyso-Gb1) in Patients with Gaucher Disease: Exploring a Novel Correlation with IgG Levels in Plasma and a Biomarker Measurement in CSF.

Gaucher disease (GD, OMIM 230800) is one of the most common lysosomal disorders, being caused by the deficient activity of the enzyme acid β-glucocerebrosidase (Gcase). Three clinical forms of Gaucher's disease (GD) are classified based on neurological involvement. Type 1 (GD1) is non-neuronopathic, while types 2 (GD2) and 3 (GD3) are neuronopathic forms. Gcase catalyzes the conversion of glucosylceramide (GlcCer) into ceramide and glucose. As GlcCer accumulates in lysosomal macrophages, it undergoes deacylation to become glycosylsphingosine (lyso-Gb1), which has shown to be a useful and reliable biomarker for the diagnosis and monitoring of treated and untreated patients with GD. Multiple myeloma (MM) is one of the leading causes of cancer-related death among patients with GD and monoclonal gammopathy of undetermined significance (MGUS) is a non-neoplastic condition that can be a telltale sign of a B clonal proliferation caused by the chronic activation of B cells. This study aimed to quantify Lyso-Gb1 levels in dried blood spots (DBS) and cerebrospinal fluid (CSF) as biomarkers for Gaucher disease (GD) and discuss the association of this biomarker with other clinical parameters. This is a mixed-methods study incorporating both cross-sectional and longitudinal elements within a cohort design with a convenience-sampling strategy. Data collection took place from January 2012 to March 2023. Lyso-Gb1 extraction from DBS involved the use of a methanol-acetonitrile-water mixture, followed by incubation and centrifugation. Analysis was performed using UPLC-MS/MS with MassLynx software version 4.2 and the control group for the DBS measurements included general newborns. CSF Lyso-Gb1 was extracted using ethyl acetate, analyzed by UPLC-MS/MS with a calibration curve, and expressed in pmol/L. Lysosomal activity in CSF was assessed by measuring chitotriosidase (Cht), and other lysosomal enzyme activities were assessed as previously described in the literature. Patients with metachromatic leukodystrophy (MLD) were used as controls. Thirty-two treated patients (twenty-nine GD1 and three GD3, all on ERT except for one GD type on SRT with eliglustat) and three untreated patients (one GD1, one GD2, and one GD3) were included. When analyzing only the treated GD1 group, a significant correlation was found between lyso-Gb1 and age (rho = -0.447, p = 0.001), ChT, and IgG levels (rho = 0.73, p < 0.001; and rho = 0.36, p = 0.03, respectively). Five GD1 patients (three females, mean age 40 years) also had their CSF collected and analyzed. The average measurement of lyso-Gb1 in CSF was 94 pmol/L (range: 57.1-157.9 pmol/L) versus <6.2 pmol/L in the control group (MLD). This is the first time, to the best of our knowledge, that lyso-Gb1 has been associated with IgG levels. While this finding reflects a risk for MGUS or MM and not only chronic plasma B-cell activation, it still requires further studies. Moreover, the analysis of CSF lyso-Gb1 levels in GD1 patients was demonstrated to be significantly higher than the control group. This raises the hypothesis that CSF lyso-Gb1 may serve as a valuable indicator for neurological involvement in GD, providing insights into the potential implications for neurological manifestations in GD, including GD1. The correlation between lyso-Gb1 and ChT levels in treated GD1 patients further underscores the interconnectedness of lysosomal markers and their relevance in monitoring.

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore present a target population for MGUS screening. This two-part study is the first study to evaluate the relationship of MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio (OR)= 1.10; 95% confidence interval (CI): 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer associated with the progression of MGUS, except for myeloid malignancies which were associated with lower risk of progression (hazard ratio (HR)=0.37; 95%CI: 0.16-0.89; p=0.028). Our findings indicate that a prior cancer are not a significant aetiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Dietary risk factors for monoclonal gammopathy of undetermined significance in a racially diverse population

AbstractMonoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma, is associated with shorter lifespan and cardiac, renal, neurologic, and immune-related comorbidities. There is little known about modifiable risk factors for this condition. To determine whether the risk of MGUS is associated with dietary factors in a racially diverse population, we conducted a US population–based case-control study from the National Health and Nutrition Examination Survey (1988-2004), which included 373 individuals with MGUS and 1406 matched controls. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. Unconditional multivariable logistic regressions were used to model associations between intake of several food groups and MGUS, with odds ratios (ORs) and 95% confidence intervals (CIs) reported for the highest relative to the lowest quantile of intake. Daily gram intake of several food and beverage groups were significantly associated with MGUS. MGUS was inversely associated with whole-grain bread, oats, and rice (OR, 0.70; 95% CI, 0.48-1.00; P < .05), fruits (excluding juice) and vegetables (OR, 0.69; 95% CI, 0.52-0.93; P = .02), vegetables (OR, 0.75; 95% CI, 0.56-0.99; P < .05), tomatoes (OR, 0.72; 95% CI, 0.51-1.00; P < .05), and cruciferous vegetables (OR, 0.44; 95% CI, 0.26-0.74; P < .01). Direct associations were observed for sugar-sweetened beverages (OR, 1.34; 95% CI, 1.00-1.78; P < .05), sugar-sweetened soft drinks (OR, 1.41; 95% CI, 1.01-1.96; P = .04), and artificially sweetened soft drinks (OR, 1.55; 95% CI, 1.04-2.33; P = .03). Our study shows that diet is potentially a modifiable risk factor for MGUS.

Clinical and Diagnostic Challenges in Patients with Concomitant Plasma Cell Disorders and Myeloproliferative Neoplasms

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell precursor disease that regularly precedes the development of multiple myeloma (MM). It accounts for about 4.5% in the entire population, however patients with myeloproliferative neoplasms (MPN) seem at a higher risk for MGUS with a reported rate of concomitant disease at 3-14%. The reason for this co-occurrence of MGUS and MPN remains unclear, and a common cell of origin has not yet been defined. Inversely, constant MPN-driven inflammation in the bone marrow microenvironment (BM) may stimulate the expansion of a pre-existing plasma cell clone thereby promoting the transition from MGUS to active MM. Here, we investigated the clinical and molecular characteristics of a comprehensive series of cases treated for MGUS/MPN overlap at our center. Methods: Patients who were diagnosed with concomitant MGUS/MM and MPN between 2006 and 2023 were identified by retrospective chart review, yielding a total of 13 cases. Results: We identified 5/13 patients with a confirmed diagnosis of MGUS and 8/13 cases with active MM, all coinciding with a diagnosis of MPN (5 polycythemia vera (PV), 4 chronic myelomonocytic leukemia (CMMol), 3 primary myelofibrosis (PMF), 1 chronic myelogeneous leukemia (CML)). Median age at diagnosis was 66 (range 44-78) years for MGUS/MM and 64 (range 43-81) years for MPN. Overall survival in our cohort was rather short at a median of 8.2 (range 0-16) years. For clinical management, anti-MM therapy was prioritized over MPN treatment in the majority of patients, with the exception of CMMol. MPN-related organ restrictions significantly limited treatment options for MM, including bleeding disorders, infectious complications and impaired hematopoiesis (in PMF). High-dose concepts were performed in transplant-eligible cases, including autologous in 4 and allogenic stem cell transplantation in 2 patients. Two out of 6 patients died under transplant (1 autologous graft failure), indicating a comparably high transplant-related mortality. Another patient died from MM progression as PMF-induced anemia did not allow for more intense treatment. To examine the evolutionary path from MGUS to MM and the potential impact on this transformation by a concomitant MPN, we next examined the clinical course of disease in each patient. Six out of 13 patients had secondary MPN after prior MGUS/MM diagnosis, 5/13 patients were diagnosed with MPN first, and for 2/13 cases BM assessment revealed coincidental findings of MPN/ MM at the same time. For the cases of secondary MPN after initial diagnosis of MM/MGUS, latency between both diseases was shorter, than vice versa (40.2 vs. 73.6 months, P=0.19). No association was observed between secondary MPN and prior treatment for MM, as only 1/6 patients was diagnosed with PV following high-dose melphalan chemotherapy, potentially pointing towards a negligible role of treatment-induced secondary primary malignancies the context of MM/MPN overlap. In contrast, MGUS progression to active MM was observed in 1 patient with hyperdiploid IgG kappa MM (including trisomy 9) and long-term coexistent JAK2-mutated PV. Another patient was diagnosed with IgG kappa MM and 9p gain along with concomitant JAK2-mutated PMF. Whole-genome sequencing (WGS) is currently ongoing for these patients to decipher the temporal relationship of MM/MGUS and JAK2-mutated MPN. Conclusions: The prevalence of MGUS/MM in MPN patients seems modestly increased as compared to the entire population. From a clinical viewpoint, overlap of both diseases poses significant challenges to healthcare providers as treatment-related mortality tends to be higher than in patients with mutually exclusive MPN/ MM. Improved understanding of the molecular interplay of both diseases will inform risk-adjusted treatment decisions and will lead to improved outcomes in this highly challenging subgroup of patients.

Monoclonal Gammopathy of Undetermined Significance and Risk of Cardiovascular Disease in US Veterans

Background: Monoclonal gammopathy of undetermined significance (MGUS) has been associated with worse overall survival. The cause of this association is unclear but may result from increased risk of cardiovascular disease (CVD) events. Population-based studies have demonstrated associations between MGUS and CVD, but these were in largely Non-Hispanic White (NHW) populations. As such, we aim to examine the association between MGUS and CVD risk in the US Veterans Health Administration (VHA) which has the largest population of non-Hispanic Black patients (NHB). Additionally, this database can capture patient outcomes with an extensive electronic medical record system. The identification of a novel risk factor for CVD will improve our ability to prevent CVD events further. Methods: This was a population-based retrospective cohort study of US Veterans using linked data from the national Veterans Health Administration and Medicare. Veterans free from CVD events were included in the analytic cohort and were followed from age 50 until they either develop CVD, they expire, or the date 12/31/2022 is reached. Veterans who died or were lost to follow up within 3 years after age 50 were excluded. The exposure is presumed MGUS diagnosis before CVD event or ever. The MGUS diagnosis was captured by a natural language processing (NLP) algorithm (previously developed by our group) based on the presence of a monoclonal protein less than 3 gm/dL and bone marrow plasma cells less than 10%. The outcome of interest was CVD event after age 50 which was identified with International Classification of Diseases (ICD)-9 and -10 codes atherosclerotic cardiovascular diseases and congestive heart failure. A multivariable logistic regression adjusting for sex, race/ethnicity, region of residence, income level, marital status, type 2 diabetes before CVD diagnosis or ever, and BMI at age 50 was performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: The analytic cohort contained 523,604 Veterans: 503,098 without MGUS, among whom 25.8% developed CVD and 20,506 with MGUS, among whom, 40% developed CVD (p&amp;lt;0.0001). The CVD events included heart failure with 18.6% (n=3,804) in the MGUS group and 8.7% (n=43,955) in the group without MGUS (p&amp;lt;0.0001). The mean age of MGUS (n=20,506) was 69.2 years and 66.8 in patients who had a CVD event (n=137,918). Compared to individuals without MGUS, individuals with MGUS had a higher proportion of being male (95.5 versus 86.5%, p&amp;lt;0.0001), non-Hispanic Black (29.7 versus 22.0%, p&amp;lt;0.0001), non-Hispanic White (55.2 versus 50.0%, p&amp;lt;0.0001), divorced/separated/widowed (36.2 versus 19.6%, p&amp;lt;0.0001), single/never married (10.6 versus 6.0%, p&amp;lt;0.0001), diabetes mellitus (38.4 versus 22.0%, p&amp;lt;0.001). The odds ratio of having a CVD in the setting of MGUS was 1.23 (95% CI: 1.19-1.26). Conclusions: MGUS was associated with an increased risk of diagnosis of cardiovascular disease for individuals aged 50 years or older. Clinicians should consider evaluation of patients with MGUS for CVD risk factors. Further studies are required to evaluate whether addressing modifiable CVD risk factors is associated with decreased risk of developing CVD in MGUS patients.

Increased Risk of Monoclonal Gammopathy of Undetermined Significance in US Military Service Members: A Case-Control Study of 1,068 Service Members Deployed to Either Europe or Iraq, with or without Reported Burn Pit and Toxic Smoke Exposure

Background:Monoclonal Gammopathy of Undetermined Significance (MGUS) is a plasma cell disorder which may lead to and in all cases precedes multiple myeloma (MM). Although, the etiology of MGUS is unknown, multiple studies have shown an association between MGUS and pesticide exposure (Kachuri et al, Int. J. Cancer 2013). Furthermore, soldiers and First Responders may be at higher risk of developing MGUS as evidenced by a 2.4-fold increased risk for MGUS in Vietnam Veterans exposed to Agent Orange (Landgren et al, JAMA Oncol. 2015) and a 1.8-fold higher risk in World Trade Center (9/11 attacks)-exposed fire fighters compared to reference populations (Landgren et al, JAMA Oncol. 2018). US Service Members deployed to the Southwest Asia theater of military operations (e.g., Iraq and Afghanistan) may have been exposed to various airborne hazards including smoke and fumes from open burn pits (chemical, paint, munitions, petroleum, plastic, rubber, medical, human, and food waste), oil well fires, and aircraft fuel/exhaust. Researchers are currently investigating the long-term consequences from these exposures. We were motivated to determine whether US Service Members deployed to Iraq were at increased risk of developing MGUS. Methods: Serum samples and clinical data (N=1,068) were attained from the Armed Forces Health Surveillance Division (AFHSD), the central epidemiologic health registry and biorepository for the US Military after IRB exemptions were granted. A total of 534 US Service Members who deployed to Iraq between January 1, 2005 and June 30, 2007 and reported burn pit exposure, smoke, burning trash, etc. on their post-deployment health assessment form (exposed cases) were matched 1:1 to 534 Members deployed to Germany (matched controls) who were never deployed to Southwest Asia and denied toxic exposure. All cases were deployed ≥ 6 months, were ≥ 35 years old at time of deployment, remained in the military ≥ 10 years and had serum available in the AFHSD repository 10 years after deployment. Matched criteria included deployment year (+/- 10 years), age (+/- 3 years), sex, service branch, military rank, and occupation category. The 10-year post-deployment samples underwent laboratory testing to screen for monoclonal protein by immunofixation (IFE) using pentavalent antisera with positive samples confirmed and typed using IFE gels (Sebia) and for serum free light chains (sFLC; Sebia) performed on the DYNEX Agility platform. IFE-positive samples underwent serum protein electrophoresis (SPEP) quantification by capillary electrophoresis (Sebia). Results:The median age of exposed Service Members was 37 years (range: 35-52) and 37 years (range: 35-55) for controls (Table 1). In both cohorts, the frequency of White (64.8%), Black (18.7%), Hispanic (7.5%), and male (89%) patients were the same as was the distribution of military occupation, rank, and service branch. The median number of days deployed for exposed vs controls was 243 and 852, respectively. There was no statistically significant difference between burn pit exposed and controls in the combined prevalence of MGUS (IFE+ monoclonal protein) and light chain (LC) MGUS (abnormal sFLC ratio), 6.7% (95% Confidence Interval (CI): 4.8-9.2%) vs 5.4% (95% CI: 3.7-7.7%), respectively (p=0.22). Similarly, there was no difference in prevalence when assessing IFE+ or sFLC+ cases separately (Table 2). The prevalence of MGUS or LC-MGUS for all 1,068 Service Members was 6.1% (95% CI: 4.7-7.7%). Conclusion:In our cohort of 534 Service Members deployed to Iraq and exposed to burn pits and other airborne toxic hazards (cases) there was no statistically significant difference in the prevalence of MGUS compared to 534 deployed to Germany (matched controls). Interestingly, the overall prevalence of MGUS/LC-MGUS in this combined deployed population was 6.1%. When taking into account that the median age at deployment was 37 years and samples were attained 10 years later (approximately at an age of 47 years), the observed prevalence is 3-fold higher than that reported in the Icelandic iStopMM study (2% in the 41-50 -year age group). Future studies are needed to further elucidate causes for the increased prevalence of MGUS/LC-MGUS in deployed US Military Service Members. This contents is the sole responsibility of the authors and do not necessarily reflect the views, opinions or policies of the US Government nor endorsement of commercial products mentioned.

Geographic Prevalence Patterns and Modifiable Risk Factors for Monoclonal Gammopathy of Undetermined Significance

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant plasma cell disorder with an etiology that is incompletely understood. Modifiable risk factors and genetic predispositions likely interact to increase MGUS risk in specific individuals and populations. Identifying geographic prevalence patterns and modifiable risk factors is critical for understanding the etiology of MGUS. The aim of this review was to outline original research on MGUS prevalence across geographic locations and modifiable risk factors. We conducted a systematic review of 39 eligible studies from PubMed®, Embase®, and Web of Science® written in English and published by February 2023. Our protocol was registered in accordance with PROSPERO guidelines. Studies were synthesized using Research Electronic Data Capture and appraised using the National Heart, Lung, and Blood Institute study quality assessment tools. The prevalence of MGUS ranged from 0.24% to 9% across geographic locations. Modifiable risk factors for MGUS include infections, autoimmune diseases, chronic inflammatory conditions, lifestyle factors, environmental exposures, and ionizing radiation. Therefore, the development of MGUS may be related to chronic antigenic stimulation and genetic aberrations that promote clonal proliferation of plasma cells. Prospective studies assessing gene–environment interactions are needed to further define risk factors for MGUS and inform screening and preventative strategies.

Nutritional Status Indices and Monoclonal Gammopathy of Undetermined Significance Risk in the Elderly Population: Findings from the National Health and Nutrition Examination Survey.

Although several studies have found dietary intake is related to multiple myeloma (MM) and its precursor status risks, the role of one's nutritional status has been ignored and its role in plasma cell neoplasm development is still unclear. This study aimed to explore the relationship between various clinical indices of nutritional status and the risk of monoclonal gammopathy of undetermined significance (MGUS) in the population. We selected 9520 participants from the NHANES III and NHANES 1999-2004 studies. Controlling nutritional status index (CONUT), prognostic nutritional index (PNI), geriatric nutritional risk index (GNRI) and body mass index (BMI) were calculated as indices of nutritional status of the participants. Associations between nutritional indices and MGUS were investigated using multiple logistic regression, subgroup analysis, and an RCS model. In our study, 266 participants had MGUS, with a prevalence of 2.79%. This study found that CONUT and PNI identified populations with poor nutritional status and had a significant positive correlation with the risk of MGUS. In multivariate logistic regression, compared with the lower CONUT score (<3) group, the OR for the group with higher scores (≥3) was 1.805 (95%CI: 1.271, 2.564). Compared with the lowest quartile group, the highest quartile PNI score group had an OR of 0.509 (95%CI: 0.290, 0.896). GNRI had no significant correlation with the risk of MGUS, with an OR of 0.737 (95%CI: 0.443, 1.227). This study found that older adults with CONUT and PNI scores indicating poorer nutrition had a higher risk of MGUS.

Risk of MGUS, a multiple myeloma precursor, in relation to food and beverage intake in the National Health and Nutrition Examination Survey (NHANES).

e20062 Background: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder (PCD) with a prevalence of 3% in adults over age 50. The annual risk of progression to multiple myeloma (MM) is 1%. Although one cohort study in Caucasians reported that diets low in certain plant-based foods were associated with MGUS (Thordardottir et al. 2018), research on diet and MGUS in a more diverse population is scarce. Given that diet can vary greatly across ethnic/racial groups, we conducted a population-based study with multiple races and ethnicities. Methods: Using the National Health and Nutrition Examination Survey (NHANES), we conducted a case-control study in 373 individuals with MGUS and 1,406 controls frequency matched on age, body mass index, NHANES cycle, sex, and race. Diet was characterized by one 24-hour dietary recall, with gram intake of individual foods and beverages aggregated into groups. MGUS status was determined by blood screening. Unconditional multivariable logistic regressions were used to model associations between MGUS and intake, with odds ratios and 95% confidence intervals reported for the highest quantile of intake. Results: Daily intake of several food and beverage groups were significantly associated with MGUS, low-risk MGUS (LRMGUS) or intermediate/high-risk MGUS (IHRMGUS). Whole-grain bread, oats, and rice; fruits and vegetables; tomatoes; and cruciferous vegetables were associated with significantly lower risk (28-78%). Sugar- and artificially sweetened beverages were associated with significantly higher risk (34-113%). Interestingly, there were more significant findings for LRMGUS than IHRMGUS, suggesting potential contributing etiologic differences for LRMGUS and IHRMGUS. Conclusions: Our study shows that low intake of whole grains, fruits and vegetables and high intake of sweetened beverages are associated with MGUS. The identification of dietary risk factors for MGUS in a diverse population is of direct public health relevance. These findings also provide rationale for exploration of mechanistic links between diet and PCDs, such as the ongoing studies NCT04920084, NCT05640843, and NCT05312255. [Table: see text]

Low Intake of Fruits and Vegetables and High Intake of Processed Meats and Juices Are Associated with Risk of MGUS in the National Health and Nutrition Examination Survey (NHANES) Database

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder with a prevalence of about 3% in adults over age 50. The annual average risk of progression to multiple myeloma (MM) is approximately 1%. MGUS has also been reported to be associated with excess risk of cardiac, renal, neurologic, and immune-related conditions. Although inflammatory or insulinemic diets or diets low in plant-based foods have been associated with risk of MM, there is limited information on dietary factors and risk of MGUS from one Icelandic cohort study which focused on Caucasians (Thordardottir et al. 2018). Given that food intake can vary greatly across ethnic/racial groups, we were motivated to conduct a large population-based study including Caucasians, African-Americans, Hispanics, Asians, Pacific Islanders, and other ethnic/racial groups. Methods Using the National Health and Nutrition Examination Survey (NHANES), we conducted a case-control study including 373 individuals with MGUS (cases) and 1,406 frequency-matched controls. Diet was characterized by 24-hour dietary recall (DR) and food frequency questionnaire (FFQ). MGUS status was determined by screening. Unconditional multivariable logistic regression analyses were used to model the association between MGUS and daily intake of macronutrients, 18 micronutrients, and nine USDA food groups from the DR, and analogous food groups from the FFQ, with odds ratios (OR) and 95% confidence intervals (CI) for MGUS as the measures of association. Results Descriptive characteristics of the study sample are shown in Table 1. Over 40% of the participants were members of racial or ethnic minorities. Among the micronutrients, only sodium intake achieved significance (Figure 1); individuals with insufficient daily sodium intake were 54% more likely to have MGUS than those with sufficient intake (OR=1.54; 95% CI=1.07-2.21), which could be indicative of individuals with kidney disease or hypertension (both associated with MGUS) or heart failure following low-sodium diets. Excessive sodium intake was not significantly associated with MGUS in this study. Daily gram intake of "Fruits, excluding juices, and vegetables" was higher in non-MGUS, with the highest quartile associated with 33% lower odds of MGUS (Q4 OR=0.67; 95% CI=0.48-0.94; p for trend=0.02). Daily gram intake of "Sugars, sweets, and beverages" was significantly associated with an increased odds of MGUS (Q4 OR=1.45; 95% CI= 1.01-2.08; p for trend=0.02). Monthly frequency of intake of "Meat, poultry, seafood, stews" (Q4 OR=1.61; 95% CI=1.03-2.50, p for trend<0.05) was associated with MGUS, with most of the effect coming from processed meat (data not shown). Frequency of intake of "Fruit juice" (Q3 OR=1.91; 95% CI=1.24-2.96; Q4 OR=1.81; 95% CI= 1.17-2.81; p for trend<0.01) was also associated with MGUS. There was a suggestion of an inverse association between monthly intake of "Bread, cereal, rice, starchy entrees, cakes" and MGUS. Compared to Q1, Q2 was significantly associated with reduced risk of MGUS (Q2 OR=0.62; 95% CI=0.41-0.96); Q3 and Q4 supported this trend but were not significant. Most of the category effect was due to dry cereals and yeast breads (data not shown). No other micronutrient or food group, measured by DR or FFQ, was found to be associated with MGUS. Conclusions Our study shows that certain dietary characteristics, including low intake of sodium, fruits and vegetables, and cereals and yeast breads, and high intake of sugars, sweets, and beverages, juices, and processed meat, are associated with MGUS. The identification of novel dietary risk factors for MGUS in a diverse population are of direct public health relevance. The findings of this study also provide rationale for exploration of mechanistic links between diet and the microbiome, immune system, metabolism, and epigenetics, such as the ongoing plant-based diet pilot study at Memorial Sloan Kettering Cancer Center (NCT04920084) and intermittent fasting study at Roswell Park Comprehensive Cancer Center (NCT05312255). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A 12 Gene Signature Accurately Predicts Multiple Myeloma Progression from Monoclonal Gammopathy of Undetermined Significance

Introduction: More than 176,000 individuals are diagnosed with multiple myeloma (MM) worldwide per year. MM is always preceded by an asymptomatic phase, monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM). MGUS is found in 2.4% of individuals ≥ 50 years. The results of long-term retrospective follow-up studies have shown a 1.0% annual risk of MGUS progressing to MM. At present, using conventional serum markers, MGUS patients can be stratified into clinical risk groups. However, these models were based on retrospective analyses of cohorts tested for a limited set of clinical variables which did not incorporate genomic properties and are inconsistent as suggested by recent studies. Our previous work has established that the GEP70 signature can identify high-risk MM patients with median survival is about 2.5 years. A robust high-risk molecular signature predicting MGUS progression is still lacking. Methods: A total of 268 MGUS patients with gene expression profiles (GEPs) were included in this study. Twenty-six progressed to MM within 10 years and were considered the high-risk group, while 242 MGUS patients not progressing to MM within 10 years were referred to as the stable group. Plasma cells were enriched from bone marrow aspirates to >85% purity using anti-CD138 immunomagnetic beads. GEP was performed with the Affymetrix U133 Plus 2.0 microarray platform, using 54,613 gene probes. Affymetrix signals MAS5.0 normalized and transformed by log-base 2 for each sample. We used 3-fold cross-validation to identify the number of genes at the top of this list, probes were ranked by q-values, which collectively maximized the concordance between risk score and MGUS progression. Gene scores were computed by subtracting the average of the expression of down-regulated genes from the average of the expression of up-regulated genes. The overall accuracy of using a gene score to predict the outcome of progression was analyzed by a receiver operating characteristic curve (ROC) and its area under the curve (AUC). MGUS progression was assessed by Kaplan-Meier curves comparing the different groups. Cox proportional hazards regression analyses were applied to evaluate the significance of the gene signature for MGUS progression. Results: Of the 54,613 probes, using q statistics at <0.01, 81 probes were significantly associated with MGUS progression. After the 3-fold cross-validation analysis, the top twelve probes that appeared in each validation and maximized the concordance between risk score and MGUS progression were included in the gene signature 12 (GS12). The up-regulated genes were MTRR (5p15.31) and BAG1 (9p13.3). The down-regulated genes were ECHDC2(1p32.3), NLRP7(19q13.42), BIRC3(11q22.2), PLEKHF1(19q12), PTPN1(20q13.13), CKAP2(13q14.3), RNF5(6p21.32), LIMA1(12q13.12), CEACAM3(19q13.2) and LOC100128079(16p12.1). The ROC analysis showed that the GS12 could accurately predict the MGUS progression in all 268 MGUS patients (AUC = 0.920). An optimal cut-point for risk of progression by the GS12 score was found to be 2.73, which identified a subset of 23 (8.6%) patients with a 10-year progression probability of 73.9%. The remainder of the 245 patients (91.4%) had a probability of progression of only 3.7%. The sensitivity and specificity were 65.4% and 97.5% respectively. Multivariate analysis showed the GS12 to be an independent risk factor for the progression of MGUS to MM. Comparing GS12 with GEP70 showed that GS12 is better at predicting progression to MM than GEP70. GEP70-defined high-risk MGUS predicted risk of progression to MM of 18% while GS12-defined high-risk MGUS raised that estimate to 73.9%. Conclusion: A gene score based upon twelve highly differentiating genes showed excellent accuracy in predicting 10-year MM progression from MGUS. Integration of gene signatures into the routine management of MGUS patients may improve the application of risk-adapted approaches to prevent progression to overt MM. We are in the process of collecting more samples and incorporating RNA-seq data to determine whether this model can be adapted to predict MGUS progression on a larger scale with current state-of-the-art technologies.

Autoimmune Diseases Are Not Associated with Monoclonal Gammopathy of Undetermined Significance: Results of the Prospective Population-Based Istopmm Study

Background: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma and related conditions. Previous registry-based studies and retrospective clinical case studies have proposed an increased risk of MGUS among patients with autoimmune diseases. However, as the clinical diagnosis of MGUS is, by definition, made when investigating the cause of unrelated symptoms, prior studies have been unable to control for selection bias. Therefore, the true relationship between MGUS and autoimmune diseases remains unknown and can only be evaluated in a screening study. Aims: To examine whether autoimmune diseases are associated with MGUS in a screened population. Methods: This study used data from Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM), a population-based screening study of MGUS. Briefly, 93% of 80,759 consented participants, representing 54% of the Icelandic population aged 40 years or older, have been screened for MGUS using serum protein electrophoresis (SPEP) and a free light chain (FLC) assay. To identify individuals in the study with a previous clinical diagnosis of MGUS, records from the two laboratories performing SPEP in Iceland were used and cross referenced with the Icelandic Cancer Registry. Diagnoses of autoimmune diseases were extracted from the Icelandic Hospital Discharge Register and the Icelandic Register of Primary Health Care Contacts, both of which have >95% completeness and accuracy. All diagnoses from the 1st of January 1999 to 31st of December 2020 were included. T-test and chi-squared test were used for univariable comparison of the prevalence of autoimmune disease among those without any MGUS (whether clinical or screened, the control group), compared with different groups: individuals with a positive screening test for MGUS and those with a previous clinical diagnosis of MGUS, as well as both groups combined. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI), adjusting for age and sex, comparing the same two groups to the control group as in the univariable analysis. Results: Among 75,422 screened samples 3,358 had MGUS and 316 light chain MGUS (LC-MGUS). Of all screened individuals, 338 had a prior clinical diagnosis of MGUS or LC-MGUS and 234 had both clinical and screened MGUS, 104 were negative at screening. Individuals with MGUS were older (median age 70 vs 61, p<0.001) than those without MGUS and more frequently male (53.5% vs 45.3%, p<0.0001). Of all participants, 12,111 (16.1%) had a diagnosis of an autoimmune disease, whereof psoriasis, rheumatoid arthritis, polymyalgia rheumatica, ankylosing spondylitis, and diabetes mellitus type 1 were most common (Table 1). In the screened population, neither MGUS nor LC-MGUS were associated with autoimmune disease compared with individuals without MGUS or LC-MGUS (controls), OR 0.98 (95% CI 0.89-1.08) and 1.07 (95% CI 0.79-1.42), respectively. However, among individuals with a prior clinical diagnosis of MGUS, we found an association with autoimmune disease, OR 1.93 (95% CI 1.44- 2.56) (Figure 1). When the clinical and screened MGUS groups were combined the results were similar to the screened group alone (Figure 1). Conclusion: In this large, prospective, population-based screening of over 75,000 individuals, we did not find an association between MGUS or LC-MGUS and autoimmune disease. However, in sharp contrast, we did find a correlation with autoimmune disease among individuals diagnosed with MGUS in a clinical setting. Our results support the hypothesis that clinical case series and prior registry-based studies showing an increased risk of MGUS among patients with autoimmune diseases reflect a detection bias. This large, prospective screening study negates the previously reported biological correlation between autoimmune disease, MGUS and LC-MGUS and shows that autoimmune diseases are not associated with MGUS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

THE USE OF LANADELUMAB AS TREATMENT IN A PATIENT WITH ACQUIRED ANGIOEDEMA

<h3>Introduction</h3> There are no FDA-approved therapies for acquired angioedema (AAE). In AAE patients whose underlying disease process is not amenable to therapy, options are limited, sometimes requiring off-label use of medications used for hereditary angioedema (HAE). Lanadelumab with rescue use of icatibant has not been officially studied for the management of AAE but has shown efficacy in HAE patients. <h3>Case Description</h3> A 75-year-old male with history of stage 1 colon adenocarcinoma in remission presented with angioedema initially attributed to apixaban used for treatment of post-COVID-19 pulmonary embolus. Despite discontinuing apixaban, he continued to experience monthly episodes of angioedema involving orofacial and gastrointestinal symptoms, requiring 4 hospitalizations and steroid, oral antihistamine, tranexamic acid, and fresh frozen plasma treatments. One episode involved airway compromise requiring emergency icatibant use and transient intubation. Diagnostic results showed low C4, C1 total protein, and C1 inhibitor function, with negative C1 auto-antibody. Subsequent testing revealed monoclonal gammopathy of undetermined significance (MGUS) of low to intermediate risk (IgG kappa subtype); treatment was not recommended given MGUS staging and risk of treatment. He was started on lanadelumab every 2 weeks with continued icatibant for rescue use and has had remission of AAE over the following 3 months. <h3>Discussion</h3> Lanadelumab in combination with rescue icatibant is emerging as an effective regimen to reduce hospitalizations and morbidity in AAE patients, particularly in patients whose underlying etiology of disease is unknown or for which treatment is not indicated. Investigation on a larger scale is warranted to better understand this therapeutic option for patients with AAE.

Myeloma precursor disease (MGUS) among rescue and recovery workers exposed to the World Trade Center disaster

An elevated risk of myeloma precursor disease, monoclonal gammopathy of undetermined significance (MGUS), was identified among Fire Department of the City of New York (FDNY) World Trade Center (WTC)-exposed firefighters. Further investigation was needed to determine if these findings were reproducible in a more heterogeneous WTC-exposed rescue/recovery workers cohort, the Stony Brook University-General Responder Cohort GRC (SBU-GRC). MGUS risk was compared between the cohorts and to published general population estimates from Olmsted County, MN, USA. In this observational seroprevalence study, odds ratios (OR) and age-standardized risk ratios (RR) of MGUS (M-spike and light-chain-MGUS combined), M-spike, and light-chain-MGUS were estimated using logistic regression. Age-standardized prevalences were calculated for white males aged 50–79; RRs were estimated by comparing risk in the WTC-exposed cohort with the Olmsted County screened cohort. SBU-GRC had elevated odds of MGUS compared with FDNY (OR = 1.38; 95%CI = 1.00–1.89). The age-standardized prevalence of MGUS was 9.0/100 persons (95%CI = 7.5–10.6), over two-fold higher than the general population (RR = 2.08; 95%CI = 1.72–2.51); the age-standardized prevalence of light-chain-MGUS was 3.5-fold higher (RR = 3.54; 95%CI = 2.52–4.97). This study adds to mounting evidence supporting an association between WTC/environmental exposures and MGUS among rescue/recovery workers. Access to MGUS screenings for the entire WTC-exposed cohort could allow for treatment interventions that improve survival.

The association of agent orange (AO) exposure with monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) progression: A population-based study.

8050 Background: With limited evidence from a single center study [n=211 (11 with AO exposure)] reporting AO exposure as a risk factor for transformation, whether or not AO exposure increases the rate of transformation from MGUS to MM is unclear. Thus, we aimed to conduct a nation-wide study to determine the association between AO exposure and the risk of MGUS to MM progression. Methods: A retrospective, matched cohort study using data from the U.S. Veterans Health Administration system was conducted. Based on a power calculation, a random sample of MGUS patients with AO exposure was selected and 1:1 matched to those with MGUS without AO exposure (matching factors: age at MGUS diagnosis, race, body mass index categories). Data abstraction confirmed MGUS and MM diagnoses. In addition, information on date of diagnosis, MGUS subtype, and monoclonal protein (M-protein) values was performed. Patients were considered to have MGUS if they had M-protein detected on serum protein electrophoresis (SPEP) with immunofixation confirmation. The association of AO exposure with progression from MGUS to MM was examined using a multivariable Fine-Gray subdistribution hazard model with death as the competing event. The covariates included M-protein at MGUS diagnosis (&gt;1.5, ≤1.5 g/dL [reference]), MGUS subtype (Immunoglobulin A, light chain, and Immunoglobulin G [reference]), and Charlson comorbidity score at MGUS diagnosis. A sensitivity analysis was conducted using inverse probability treatment weighted survival analysis to evaluate the robustness of the conclusion. Results: After excluding individuals with no confirmed MGUS or M MGUS subtype, a total of 563 MGUS patients with AO exposure and 563 matched controls were included. No statistically significant difference was observed in the progression of MGUS to MM between the AO exposed group and control group (adjusted hazard ratio (aHR) 0.78, 95% confidence interval (CI) 0.53 to 1.17). The sensitivity analysis demonstrated consistent results. Conclusions: Our carefully designed study does not show an association between AO exposure and progression of MGUS to MM in a national cohort of Veterans. [Table: see text]

Autoimmunity, Infections, and the Risk of Monoclonal Gammopathy of Undetermined Significance.

Various epidemiological studies, including case reports and -series in addition to larger, population-based studies, have reported an increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma in individuals with a prior history of immune-related conditions. This is believed to support the role of chronic antigen stimulation in the pathogenesis of these conditions. In this short review, we summarize some of the largest population-based studies researching autoimmune diseases, infections, and the subsequent risk of MGUS, and discuss our understanding on its etiology and pathogenesis. Furthermore, we highlight important methodological limitations of previous studies in the field, but almost all studies on MGUS have been based on clinical, possibly biased, cohorts. Finally, we discuss future directions in researching the associations of MGUS and other disorders, including immune-related conditions, where screening studies play an important role.

A genetic risk score of alleles related to MGUS interacts with socioeconomic position in a population-based cohort

Environmental, genetic, and social factors are suggested to jointly influence monoclonal gammopathy of undetermined significance (MGUS), a precursor of multiple myeloma. Aim of this study was to investigate interactions between MGUS-related genetic variants and socioeconomic position (SEP) indicators education and income on MGUS in a population-based study. Two different MGUS-related genetic risk allele sum scores (GRS) were calculated based on recent genome-wide meta-analyses. Odds Ratios (OR) were estimated in 4329 participants including 238 MGUS cases to assess associations and multiplicative interaction. The relative excess risk due to interaction (RERI) was calculated to assess additive interaction. Both GRSs were associated with MGUS. A multiplicative interaction between one GRS and education was observed with genetic effects of OR 1.34 (95% CI 1.11–1.62) per risk allele in the highest and OR 1.06 (95% CI 0.86–1.31) in the lowest education group. A RERI of 0.10 (95% CI 0.05–0.14) also indicated additive interaction. Further, additive GRS by income interaction (RERI 0.07; 95% CI 0.01–0.13) for the same GRS was also indicated. Results indicate interaction between MGUS-related genetic risk and SEP. Non-genetic MGUS risk factors more common in higher education groups may influence the expression of MGUS-related genetic variants.

Screening for Monoclonal Gammopathy of Undetermined Significance: A Population-Based Randomized Clinical Trial. First Results from the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) Study

Background:Cancer screening is performed worldwide for several malignancies. Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM) and related lymphoproliferative disorders (LP). However, less than 5% of all MM patients are diagnosed during their precursor state and individuals who develop MM while being monitored for MGUS have better overall survival and fewer complications, compared to MM patients diagnosed without knowledge of MGUS. Thus, population-based screening for MGUS could identify candidates for early treatment of MM/LPs. To evaluate whether systematic screening is beneficial, we performed the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, the first population-based screening study for MGUS that includes a randomized clinical trial (RCT) of follow-up and treatment strategies.Methods:All living residents of Iceland on September 9th, 2016 who were born before 1976 (N=148,708) were invited to participate. Of those, 80,759 (54.3%) provided informed consent for screening. Serum samples were collected from participants alongside clinical blood sampling in the Icelandic health service between September 2016 and the end of 2020. All samples were shipped to the Binding Site in Birmingham, UK, for screening. Samples were tested for M-proteins by capillary zone electrophoresis and immunofixation electrophoresis performed to confirm and characterize suspected M-proteins. Free light chains (FLCs) were measured using the FreeLite® assay. Individuals with a previous diagnosis of MM/LPs/MGUS (N=237) were excluded. Per protocol and informed consent, participants with MGUS were randomized to one of the three study arms: Arm 1 where participants are not contacted; Arm 2 where individuals are followed based on current guidelines; and Arm 3 where individuals are followed with a more intensive diagnostic and monitoring strategy. Participants who progress are offered early treatment. All participants repeatedly answered questionnaires on quality of life and mental health.Results:A total of 75,422 participants (93.4%) provided a serum sample for screening. Of those, 3,725 (4.9%) had MGUS. The prevalence of MGUS was dependent on age with 2.3%, 6.2%, and 12.9% diagnosed in age groups 40-59, 60-79, and 80-103 years, respectively. The prevalence of MGUS was higher in males, 5.9% vs 4.1% (p<0.0001). Most individuals with MGUS had either low-risk (38%) or low-intermediate (36%) risk MGUS, followed by high-intermediate (26%) risk MGUS. High-risk MGUS was only present in 0.2% of MGUS cases (n=9).The RCT includes 3,487 newly diagnosed MGUS individuals with 1164, 1159, and 1164 individuals in arms 1, 2 and 3, respectively (Table). The median age at diagnosis was 69 years in arms 1 and 2, and 70 years in arm 3. Females constituted 45.9% and the isotypes were IgG (50%), IgA (10%), IgM (18%) and biclonal (8%). The median M-protein concentration was 0.34 g/dL. A total of 428 light-chain MGUS cases were randomized. The demographic distribution was well balanced between the three arms.After a median follow-up of 3 years, 194 patients in the RCT have been diagnosed with any LP: 9 in arm 1, 92 in arm 2, and 133 in arm 3 (p<0.001). The participants in arm 1 were diagnosed with smoldering Waldenström's macroglobulinemia (SWM)(N=2), WM (N=2), chronic lymphocytic leukemia (CLL) (N=1), and MM (N=4). Participants in arm 2 were diagnosed with amyloidosis (N=1), SWM (N=18), WM (N=2), CLL (N=2), non-Hodgkin lymphoma (NHL) (N=1), smoldering MM (SMM) (N=56), and MM (N=12). Participants in arm 3 were diagnosed with amyloidosis (N=2), SWM (N=22), CLL (N=5), NHL (N=6), SMM (N=82), and MM (N=16). The difference between study arms was statistically significant for all LPs combined, and for SWM, SMM, and MM (Table).Conclusion:In this large prospective population-based screening study including >75,000 screened persons, we have identified 3,725 individuals with monoclonal gammopathy. In the RCT, after 3 years of follow-up, we show that active screening identifies significantly higher number of individuals with full-blown malignancy and smoldering disease, illustrating the fact that early detection and intervention is achievable. Although our findings are encouraging, until final results of the iStopMM study become available, including data on survival and quality of life, we advise against systematic MGUS screening in healthy individuals. [Display omitted] DisclosuresKristinsson: Amgen: Research Funding; Celgene: Research Funding. Kampanis: The Binding Site: Current Employment. Hultcrantz: Curio Science LLC: Consultancy; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Intellisphere LLC: Consultancy. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy. Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Celgene: Research Funding; Janssen: Honoraria; Janssen: Other: IDMC; Amgen: Honoraria; Takeda: Other: IDMC; Amgen: Research Funding; GSK: Honoraria.

Relationship and Susceptibility to Serious Infections Among Monoclonal B-Cell Lymphocytosis (MBL), Monoclonal Gammopathy of Undetermined Significance (MGUS), and Clonal Hematopoiesis (CH) Premalignant Conditions

Relationship and Susceptibility to Serious Infections Among Monoclonal B-Cell Lymphocytosis (MBL), Monoclonal Gammopathy of Undetermined Significance (MGUS), and Clonal Hematopoiesis (CH) Premalignant Conditions

Association of Progression Patterns in Monoclonal Gammopathy of Undetermined Significance (MGUS) with Outcome in Multiple Myeloma: A Cohort Study of over 35 Years

Introduction: Guidelines suggest following monoclonal gammopathy of undetermined significance (MGUS) according to risk of multiple myeloma progression. Follow-up of low-risk MGUS is debated as progression risk is low. Worse myeloma-related outcome was observed in patients followed for low-risk MGUS, potentially due to less optimal follow-up (Bianchi et al. Blood 2010, Sigurdardottir et al. Jama Oncology 2015). However, it is not clear if progressing low-risk MGUS by its nature displays more aggressive biological behavior. To gain better understanding of progression patterns in MGUS, we investigated, independent of follow-up, whether progression from low-risk MGUS is associated with worse outcome in multiple myeloma. The main outcome was overall survival from the time of myeloma diagnosis.Methods: The Northern Sweden Health and Disease Study (NSHDS) is a longitudinal prospective cohort with more than 100,000 participants. Typically, NSHDS participants donate repeated blood samples at intervals of several years. Samples are frozen within one hour and stored at -80° C at Umea University Hospital. Linkage to the Swedish Cancer Registry facilitated identification of myeloma patients with two pre-diagnostic samples in NSHDS (N = 61). Of these, we screened repeated pre-diagnostic samples using protein- and immunofixation electrophoresis and free light chain assays. We identified 42 individuals who had detectable monoclonal gammopathy in both pre-diagnostic samples without MGUS follow-up before myeloma diagnosis, allowing to investigate natural progression patterns in relation to outcome. Overall survival was determined using Kaplan-Meier plots. Hazard ratios and 95% confidence intervals were calculated using multivariable Cox regression including known prognostic factors. Fisher's exact test was used to compare categorical variables.Results: The first pre-diagnostic sample was collected in November 1986 and the last follow-up since myeloma diagnosis was in February 2021, resulting in a 35-year study duration. Median age at myeloma diagnosis was 62 (range 48-84) with a median follow-up of 7 years (range 0.2-18). At first pre-diagnostic blood draw, 12 had low-risk and 30 had MGUS of other risk (Mayo Clinic criteria). Characteristics at myeloma diagnosis except sex were similarly distributed between the two groups. Comorbidities, myeloma treatment and access to novel drugs were balanced between groups. Bone disease (osteolytic lesions and/or vertebral compression fractures attributable to myeloma) at myeloma diagnosis was more common in patients who had low-risk MGUS at first pre-diagnostic blood draw (P = 0.04). This association was pronounced excluding light chain myeloma (P = 0.01). Access to other radiographic imaging than conventional skeletal survey such as CT or MRI was similar for both groups.In low-risk vs. other MGUS, median overall survival since myeloma diagnosis was 2.3 (95% CI, 1.8-2.9) years and 7.5 (95% CI, 4.8-10.2) years (Figure A). Results were similar investigating overall survival since frontline therapy start (excluding 5 patients not requiring therapy) (Figure B). Sex and bone disease were not associated with survival.At repeated pre-diagnostic blood draw (in median 3.7 years prior myeloma diagnosis), 67% vs. 19% had low- or low-intermediate risk MGUS in patients with low-risk vs. other MGUS at first pre-diagnostic blood draw (P = 0.01), suggesting more rapid progression close to myeloma diagnosis in patients with low-risk MGUS at first blood draw. Investigating this further, we plotted M spikes in low-risk vs. other MGUS of IgG isotype (Figures C-D). M spike trajectories were largely similar between groups, although the annual median M spike increase from repeated pre-diagnostic blood draw to myeloma diagnosis was 6.0 g/L in low-risk vs. 2.3 g/L in other MGUS (P = 0.14).Conclusions: Progression from low-risk MGUS is, independent of MGUS follow-up, associated with a higher proportion of bone disease and worse survival. Based on the known phenotypic heterogeneity in multiple myeloma, we speculate that low-risk MGUS in case of malignant progression belongs to a group of more aggressive tumors. Our results need to be interpreted carefully because of the small sample size. Replication and further investigation are needed. If replicated, these findings could help to improve current MGUS follow-up strategies, which are solely based on progression risk. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.