Light-chain Monoclonal Gammopathy Of Undetermined Significance Research Articles

Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). Icelandic population of adults aged 40 years or older. 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. The prediction model will require external validation. This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. International Myeloma Foundation and the European Research Council.

Monoclonal Gammopathy of Undetermined Significance and the Risk of Thrombotic Events: Results from Istopmm, a Population-Based Screening Study in Iceland

Introduction: Multiple myeloma (MM), Waldenström's macroglobulinemia (WM), and related disorders have been associated with excess risk of thrombosis. Furthermore, medications used to treat these disorders, in particular immunomodulatory agents, have been associated with excess thrombotic risk. Monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic precursor of MM, WM, and related disorders, has also been associated with arterial and venous thrombosis. However, prior studies have been based on cohorts where MGUS was diagnosed as part of the work-up for other unrelated medical disorders. We have shown that these cohort have biased selection of individuals with chronic disease, including autoimmune disease, heart failure, endocrine disorders and more. This selection bias may have led to false associations or overestimation of the relationship of MGUS and thrombotic events. Aim: To evaluate the relationship of MGUS and thrombosis in a screened cohort of individuals with MGUS. Methods: Data were obtained from the Iceland screens, treats, or prevents multiple myeloma study (iStopMM), a population-based screening study for MGUS and a randomized trial of follow-up strategies with the aim of evaluating the benefits and harms of MGUS screening. As part of the study 75,422 Icelandic residents 40 years and older (54% of the underlying population) have provided their informed consent for the study and were screened by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. The cohort was crosslinked to population-based Icelandic government registries that includes all diagnoses made in the universal healthcare system, recorded as international classification of diseases (ICD) 10 codes. The study exposure was MGUS at screening and the outcome was venous and arterial thrombosis, defined as recorded ICD-10 codes. Events recorded within 90 days of each other were considered the same event. We further analyzed subgroups of M protein isotype and light chain (LC) MGUS. We followed participants prospectively after the date of screening to arterial and venous thrombosis as the endpoint and censoring at death, progression to MM, WM, and related disorders, or end of follow-up. Hazard ratios (HR) for time to first thrombotic event were estimated using Cox regression models, while hazard ratios for recurrent thrombotic events were estimated using mixed-effects Cox regression models with a random intercept. Both prospective analyses were adjusted for age as a non-linear variable and sex. In a secondary analysis, M-protein concentration was included as a non-linear variable into similar models that were restricted to those with MGUS with an M-protein. Results: Of the 75,422 screened, 3,353 had MGUS with an M-protein, here termed heavy chain (HC) MGUS, and 315 had LC MGUS. Over a median follow-up of 3.67 to 3.90 years, depending on the outcome of interest, 263 and 3,557 arterial events (20.4 and 13.5 per 1,000 person years) and 260 and 3,092 venous events (20.2 and 11.7 per 1,000 person years) were observed in those with and without MGUS respectively. MGUS was found to be associated with venous thrombotic events (HR: 1.31; 95% CI: 1.08-1.57), in particular deep vein thrombosis (HR:1.46; 95% CI: 1.12-1.90). Of the different MGUS subtypes, this association was only observed in non-IgM MGUS. The results were similar in the recurrent events analysis. IgM MGUS was found to be associated with a higher of peripheral arterial embolic events (HR: 2.86; 95% 1.04-7.85) but this association was not observed in the recurrent event analysis. M-protein concentration was not correlated with the risk of thrombotic events. Discussion: In this large population-based study including more than 75,000 individuals screened for MGUS, we found that MGUS, and particularly non-IgM MGUS, was associated with venous thrombotic events. Interestingly, the size of the M-protein spike was not associated with a higher risk for thromboembolic events. Further studies are needed to identify the underlying mechanisms with the goal of identifying subgroups of the MGUS population that may require interventions to prevent thrombotic events, potentially improving the survival and quality of life of those with MGUS.

Revised Definition of Free Light Chains in Serum and Light Chain Monoclonal Gammopathy of Undetermined Significance: Results of the Istopmm Study

Background: Serum free light chain (FLC) measurement, consisting of serum free kappa, serum free lambda, and a calculated FLC ratio (kappa/lambda), plays a pivotal role in the diagnosis, risk stratification and management of plasma cell disorders. Light chain monoclonal gammopathy of undetermined significance (LC-MGUS), is defined as abnormal FLC ratio with elevation of the involved FLC without evidence of heavy chain M protein or end-organ damage attributed to the plasma cell disorder. Several years ago, reference intervals for serum kappa (3.3-19.4 mg/L) and lambda (5.7-26.3 mg/L) FLC and FLC ratio (0.26-1.65) were defined in a small retrospective cohort (N = 282) of healthy individuals. Limitation of these reference intervals include inaccurate distributions among individuals with impaired kidney function. Recently, we addressed this matter in a large population-based study focusing on individuals with estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m 2, the results of which led to redefined reference intervals for patients with chronic kidney disease (Long et al, Blood Cancer J. 2022). Here, using a large cohort (N=41,882) of screened individuals, we aimed to determine FLC reference intervals in individuals with normal kidney function (eGFR ≥ 60 mL/min/1.73m 2). Methods: Data were collected from the ongoing Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, which focuses on population-based screening for MGUS. A total of 75,422 individuals aged ≥ 40 years (representing 51% of this age group in the Icelandic population) were screened for MGUS by serum protein electrophoresis, immunofixation, and serum FLC assay (Freelite®), and two-thirds of MGUS cases were randomized to active follow-up. Participants' eGFR was calculated using serum creatinine (CKD-EPI) closest to the time of screening. Participants with heavy chain M protein, known lymphoproliferative disorder, unknown eGFR or eGFR < 60 mL/min/1.73m 2, were excluded. The 0.5 and 99.5 percentiles of kappa FLC, lambda FLC, and the FLC ratio distributions were assessed for the whole group, and subgroups of age, sex, and different levels of eGFR. A nonparametric bootstrapping method was used to calculate the 95% confidence intervals. Partitioning was determined based on the proportion of subgroups (age, sex and eGFR) outside the whole group reference interval. Results: After application of the exclusion criteria, 41,882 participants were included for further analysis. The median (interquartile range, IQR) serum free kappa was 14.3 (11.6-17.8) mg/L, serum free lambda 14.2 (11.6-17.5) mg/L, and the FLC ratio was 1.02 (0.85-1.21). The median (IQR) age was 60 (52-68) years, eGFR 84 (74-94) mL/min/1.73 m 2, and 43% were male. A strong correlation was found between age and serum kappa FLC (ρ = 0.27, p < 0.001), lambda FLC (ρ = 0.14, p < 0.001), and the FLC ratio (ρ = 0.16, p < 0.001). Use of standard reference intervals yielded abnormal results for 17.5%, 3.9%, and 4.5% of serum kappa, lambda, and FLC ratio determinations, respectively, and a prevalence of LC-MGUS of 2.0% (96% kappa and 4% lambda). Based on these findings, we established new reference intervals for serum kappa and lambda FLC and FLC ratio, partitioned by age < 70 years and ≥ 70 years (Table). Utilizing the new reference intervals the crude prevalence of LC-MGUS was 0.3% (54% kappa and 46% lambda), yielding a relative decrease of 83%. Among the group of individuals diagnosed with LC-MGUS based on standard reference intervals who did not meet the diagnostic criteria using our revised reference intervals - none had progressed to a lymphoproliferative disorder after a median follow-up time of 42 months. Conclusion: Based on prospective screening of more than 40,000 individuals and after 3.5 years of follow-up, we show that standard reference intervals for serum FLC and FLC ratio appear inaccurate for persons with preserved kidney function. We propose a revision of the reference intervals for serum FLC and FLC ratio, and a new definition of LC MGUS (Figure). Implementation of new reference intervals will decrease the rate of false positive diagnosis of LC-MGUS in individuals with preserved kidney function by more than 80%. This, in turn, will reduce the unnecessary psychological and financial burden driven by clinical evaluation and lifelong monitoring of these individuals.

Prevalence of MGUS in Rural Indian Population: Results of Simple (IMAGe-002A) Study

Introduction: The incidence of monoclonal gammopathies is rising across the globe. Although the prevalence of monoclonal gammopathy of undetermined significance (MGUS) has been evaluated in two hospital-based studies in India, no data exists on its prevalence in community-based settings amongst the rural Indian population. Objectives: To determine the prevalence of MGUS in a rural Indian population in a community-based setting. Methods: A cross-sectional study was conducted in an agrarian village in India covering a perimeter of 24.76Km and 4588.3 hectares with an 89.2% population coverage for adults more than 45y spending 12096 man-hours as part of SIMPLe ( Screening Intervention for Myeloma and Prevention of Lifestyl e diseases) study under the aegis of Indian Myeloma Academic Group e (IMAGe) registered vide CTRI/2023/03/051220. For the complete study population, demographic details, medical history, and blood samples were collected after a thorough medical examination. Hemogram, biochemistry (Liver and renal function tests), and serum protein electrophoresis (SPEP) were universally performed in all individuals. Serum immunofixation electrophoresis (SIFE) was performed for those with abnormal SPEP graphs (those with M spike and those with abnormal bulges in beta-2 or gamma region suspicious of MGUS). Patients with monoclonal protein on SPEP or SIFE were further assessed for any features of smoldering/ multiple myeloma. The data was analyzed using JMP ver. 16.0.0. Results: The prevalence of MGUS in the study population was 1.75%. The mean age of individuals with MGUS was 63.4±5.2y with male preponderance (60%). The mean Hb was 12.39±1.8g/dL with none of the patients having any renal dysfunction. None of the patients fit into the criteria for smoldering or multiple myeloma using IMWG criteria. Among those with MGUS, the distribution of Heavy and light chains was IgG - 83.33%, IgA - 16.67% with none having IgM/ IgD paraprotein, Kappa - 50%, and Lambda - 50%. Two individuals only had light chain MGUS. Conclusion: Our study provides a comprehensive description of the prevalence of MGUS in a rural community setting in India. The background prevalence is much less compared to the Western (both USA ~3% and European~5%) population.

Monoclonal Protein Concentration and Risk of Multiple Myeloma: Is 0.5 g/DL the New 1.5?

Introduction : Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic clonal plasma cell disorder with a risk of progression to multiple myeloma (MM). To provide an accurate prognosis, monoclonal protein (M-protein) concentration has been used to assess risk of progression to myeloma. Current risk models developed from stored serum samples in a predominately white population of patients indicated a low risk of progression (less than 1% per year) in patients with M-protein of <1.5 g/dL. Little is known about M-protein concentration and risk of progression in patients tested during routine clinical care in a more diverse population. We assessed the outcomes of MGUS five years after diagnosis, and determined the association between baseline characteristics and the rate of progression to MM. Methods: We used data from national Veterans Health Administration system to identify patients diagnosed with MGUS from 1999-2021 and were followed from MGUS diagnosis until progression, death, or the date 7/11/2023 was reached. MGUS diagnosis and progression to MM was confirmed utilizing a natural language processing algorithm. We included patients of black and white race and those with IgG, IgA, or light chain MGUS. The exposure was M-protein concentration at MGUS diagnosis, stratified by ≤0.5, >0.5-≤1.0, >1.0-≤1.5, >1.5 g/dL. We plotted the cumulative incidence function curve and used a multivariable Fine-Gray sub distribution hazard model with progression at 5 years as the event of interest, and death as a competing event. Covariates included sex, race, MGUS type, age, body mass index (BMI), diabetes, renal disease, and other comorbidities summarized by Charlson Comorbidity Index at MGUS diagnosis. Results: We included 15,520 patients with MGUS. The mean age at the diagnosis was 71.1. IgG subtype was more common (83.2%) than IgA (12.7%), and light chain (4.1%). 19.6% and 39.5% of patients had renal disease and diabetes, respectively. Black veterans represented 5600 (36.1%) of the cohort. At 5 years, 26.6% of veterans with an M-protein of >1.5 g/dL were diagnosed with myeloma, compared to 11.7% with 1.1-1.5 g/dL, 6.9% with 0.6-1.0 g/dL, and 3.3% with ≤0.5 g/dL. In multivariable models an M-protein >1.5 was associated with a greater risk of progression compared to ≤0.5 (multivariable-adjusted Hazard Ratio [aHR] 9.76, 95% Confidence Interval [CI] 8.37-11.40). Overall, increasing age was shown to have lower risk of transitioning to MM at 5 years with aHR of 0.983 (95% CI 0.978-0.988). Conclusion: In this modern cohort, only an M-protein of ≤0.5 g/dL was associated with a less 1% per year risk of developing MM. Conversely, 26.6% of veterans with an M-protein level >1.5 g/dL developed MM at 5 years. Risk of MM in patients clinically evaluated for MGUS may be higher than previously thought and new models of MM progression should be developed.

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.

The force awakens, but questions remain: The future of MGUS.

The force awakens, but questions remain: The future of MGUS.

Association between excess body mass index trajectory and change in monoclonal protein level in patients diagnosed with monoclonal gammopathy of undetermined significance.

10538 Background: Obesity is a known risk factor for the development of multiple myeloma (MM) and for progression of its asymptomatic premalignant state, monoclonal gammopathy of undetermined significance (MGUS) to MM. Prior studies have demonstrated that monoclonal protein (M-spike) at MGUS diagnosis as well as high M-spike velocity within a year following MGUS diagnosis predict progression of MGUS to MM, making M-spike a useful, readily available, and less invasive (compared to bone marrow biopsy) marker to assess progression risk. However, no studies have evaluated to what extent exposure to high body mass index (BMI) over time influences M-spike trajectory. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing-based algorithm to confirm MGUS diagnosis and progression to smoldering MM or MM. MGUS patients without IgM or IgD subtype or Diabetes Mellitus and were black or white were included in the analysis. Other exclusion criteria were progression within 5 years of MGUS diagnosis, patients without M-spike level within a year before or after MGUS diagnosis, and patients without BMI data 3 years or more after MGUS diagnosis. The exposure was the trajectory of excess BMI (defined as BMI > 25 kg/m2), defined by an area under the curve (AUC) of excess BMI during the 5 years following MGUS diagnosis. The outcome was continuous M-spike trajectory post-MGUS diagnosis since a prior study demonstrated that this was a reliable marker for progression risk A multivariable mixed model was used to estimate the association of excess BMI trajectory AUC with M-spike trajectory to control for correlation between M-spike values overtime. The covariates included BMI at MGUS diagnosis, M-spike level ( > = 1.5g/dL) at MGUS diagnosis, age at MGUS diagnosis, sex, race, MGUS heavy chain subtype, and light-chain MGUS. Results: After applying the inclusion and exclusion criteria, the analytic cohort consisted of 6757 MGUS patients. Our multivariable analysis demonstrated a positive association between excess BMI trajectory and increasing M-spike trajectory (β = 0.005, p = 0.007). Conclusions: In patients diagnosed with MGUS, increasing BMI over time following MGUS diagnosis was associated with increasing M-spike level. This further supports the relationship between obesity and weight gain in the pathway of MGUS to MM progression.

Abstract 1960: Racial differences in the association of metformin use with progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus

Abstract Background: Metformin is an oral antihyperglycemic with possible antineoplastic properties based on preclinical and retrospective studies. A retrospective study of Veterans demonstrated a reduction in monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) progression in patients with diabetes mellitus (DM) treated with metformin for ≥4 years. However, it is unclear whether there are racial differences to this effect of metformin. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing-based algorithm to confirm MGUS diagnosis and progression, including smoldering MM and MM. Only patients with DM, IgG, IgA, or light chain MGUS, and black and white patients were included in the analyses. We excluded patients who experienced progression within 6 months of MGUS diagnosis, patients who were diagnosed with MGUS before DM diagnosis, and patients who died, progressed to MM, or were lost to follow up within four years of MGUS diagnosis. We defined metformin users as those who had metformin use for ≥4 years after DM diagnosis and before MM development. Cumulative incidence functions (CIF) were stratified by metformin use status. Gray’s test was performed to detect the difference between the two functions. The association between metformin use and progression was estimated by multivariable-adjusted hazard ratio (aHR) using Fine-Gray distribution hazard model with death as a competing event. The covariates included age, BMI, monoclonal protein (M-spike) level (≥1.5g/dL), creatinine, and glycated hemoglobin (HbA1c) at MGUS diagnosis, as well as sex, race, MGUS heavy chain subtype, light-chain MGUS, and Charlson Comorbidity Index. Results: Our NLP algorithm confirmed 19,551 patients with DM and MGUS. After applying our inclusion and exclusion criteria, we had 13,068 (35% black and 65% white) patients of which, 4,268 (26.2% black and 36.2% white) were metformin users. Cumulative incidence function was stratified by metformin use status were statistically significant different (p=0.04) with a lower progression rate for metformin users (see Fig). The multivariable analysis demonstrated a statistically significant reduction in progression with metformin use in the overall cohort (aHR 0.79; 95% CI 0.67-0.95). Further multivariable analyses showed that metformin use was associated with a significant reduction in progression rate in white patients (aHR 0.73; 95% CI 0.58-0.91) but not in black patients (aHR 0.90; 95% CI 0.69-1.17). Conclusions: For patients with DM and MGUS, ≥4 years of metformin use was associated with a reduced risk of progression of MGUS to MM in white patients but not in black patients. Citation Format: Lawrence W. Liu, Nikhil Grandhi, Mei Wang, Theodore Thomas, Akhil Kumar, Kristin Vargo, Kristen M. Sanfilippo, Graham Colditz, Su-Hsin Chang. Racial differences in the association of metformin use with progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1960.

Abstract 5925: Prevalence of clonal hematopoiesis in patients with monoclonal gammopathy of undetermined significance

Abstract INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of progeny derived from hematopoietic stem cells that have acquired somatic mutations at a VAF greater than 2%. CHIP manifests in 10% of patients older than 65 and is associated with an increased risk of progression to malignancies such as the MDS or AML. Although the risk factors for developing CHIP remain incompletely defined, they include prior exposure to chemotherapy and a history of smoking. Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the abnormal growth of clonal plasma cells in the bone marrow and carries a risk of 1% for progression to multiple myeloma (MM) per year. Like CHIP, it becomes more prevalent with age and is associated with smoking. Additionally, patients with MM have demonstrated an increased risk for malignancies. Thus, an examination for a correlation between CHIP and MGUS promises to reveal a link between these two pre-malignant conditions. A recent study did not demonstrate such an association, but this study was performed in a very elderly population and may not be applicable to younger patients. In this study, we aim to assess the relationship between CHIP and MGUS in a population-based cohort of MGUS patients seen at UT Southwestern Medical Center. METHODS: To evaluate an association between CHIP and MGUS, we collected bone marrow samples from 37 patients diagnosed with MGUS. We employed a hybridization capture-based next generation sequencing assay in order to detect CHIP. We identified 24 genes known to cause CHIP in adults. We also evaluated patients risk for developing MM after having been diagnosed with CHIP. RESULTS: The mean age was 68, (range 26-92). 22 patients were white, 8 were black and 3 Hispanic/Latino. 17 patients had IgG, 7 had IgA, 3 had IgM, 3 had biclonal gammopathy and 7 light-chain MGUS. We identified 18 mutations to validate the presence of CHIP in 10 (27%) patients, with the most frequent being DNMT3A (7 patients) and TET2 (5 patients). Other common mutations noted were PPM1D (2), GND1 (1), SF3B1 (1), ASXL1 in (1), and NRAS in (1). 3 out of the 10 patients harbored 2 mutations and 1 harbored 4 mutations. History of chemotherapy (n=6) and smoking (n=14) was taken into consideration to determine the relative risk of patients with MGUS developing CHIP. We found that those who had a prior history of smoking and chemotherapy displayed a higher risk of CHIP. CONCLUSION: There was no significant association between CHIP and MM progression. Our analysis showed 1 patient with CHIP progression and 2 without CHIP progression. Because the rates of CHIP and MGUS are positively correlated with characteristics like aging and a history of smoking, we expected to see high rates of CHIP in patients within our cohort. However, our data suggests that CHIP is frequent (27%) in MGUS patients, but larger future cohorts need to be evaluated to validate this association. Citation Format: Vianey Quaney, Benjamin Kroger, Aishwarya Sannareddy, Umar Khan, Fatma Kalkan, Robert H. Collins, Yazan F. Madanat, Madhuri Vusirikala, Yi Huang, Farrukh T. Awan, Praveen Ramakrishnan, Aimaz Afrough, Larry D. Anderson, Stephen S. Chung, Gurbakhash Kaur. Prevalence of clonal hematopoiesis in patients with monoclonal gammopathy of undetermined significance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5925.

Monoclonal Gammopathy of Undetermined Significance in Patients With Transthyretin Amyloidosis (ATTR): Analysis Using the iStopMM Criteria.

To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin amyloid (ATTR). We used the iStopMM study revised reference ranges for serum free light-chain (sFLC) corrected for eGFR to identify ATTR patients with light-chain MGUS (LC-MGUS). Characteristics and frequencies of the ATTR cohort with underlying MGUS was compared to a cohort of MGUS patients without ATTR. A retrospective analysis of ATTR and MGUS patients evaluated at our center between January 2014 to December 2021. A total of 149, predominantly male (87.5%) ATTR patients with a median age of 82 were included. This cohort was compared to 228 MGUS patients. Of the 149 ATTR patients, 27 (18.1%) had coexisting MGUS. Among ATTR patients with MGUS, 12/27 (44%) had LC-MGUS based on sFLC abnormalities assessed using the iStopMM reference ranges. Of the MGUS only cohort, 44/228 (19.3%) met criteria for LC-MGUS. Utilizing the iStopMM reference ranges, 6 ATTR patients did not meet criteria for abnormal sFLCs, uncovering a 20% false-positive rate. We noted higher rates of MGUS, particularly LC-MGUS, among ATTR patients when compared to our MGUS only cohort. The high prevalence remained after utilizing the iStopMM sFLC corrected for eGFR reference ranges. Additionally, 6 ATTR patients with renal-dysfunction would have met MGUS criteria if not evaluated using the iStopMM revised measures. These findings emphasize careful interpretation of sFLC abnormalities and encourage providers to keep ATTR on the differential when work-up uncovers sFLC aberrations.

Excessive Immunoglobulin Lambda (λ) Light Chain Production with Thrombocytopenia and Anaemia in a Patient with Smoldering Multiple Myeloma: A Case Report

Smoldering Multiple Myeloma (SMM) is defined as focal premalignant plasma cell proliferation in the bone marrow, along with the presence of monoclonal or biclonal protein bands in the patient’s serum. The current patient complained of severe weakness six months after knee arthroplasty. The patient exhibited a monoclonal (M-1) band on Serum Protein Electrophoresis (SPEP), which was observed in the γ-globulin region in combination with γ-heavy chains. Another protein band (M-2) was identified in the β-globulin region. These paraproteins were later confirmed by Immunofixation Electrophoresis (IFE), and both proteins reacted with anti-λ antibody. The concentration of the M-1 band was 32% (2.82 gm/dL), while the concentration of the M-2 protein band was 7.9% (0.7 gm/dL). Additionally, the total serum proteins measured 8.84 gm/dL. The plasma cell count in the Bone Marrow (BMPC) was approximately 20%. Provisionally, the patient was diagnosed as a case of gammopathy, with non-IgM Monoclonal Gammopathy of Undetermined Significance (MGUS), light chain MGUS, SMM, and MM considered in the differential diagnosis. However, the final diagnosis for the current patient was SMM. The patient responded well to treatment with cyclophosphamide and prednisone.

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 Association between Body Mass Index Trajectory and the Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Background: Obesity is a known risk factor for multiple myeloma (MM), as prior studies have shown that body mass index (BMI) greater than 25 kg/m2 (at a fixed time point) increases the risk for MM and its premalignant condition, monoclonal gammopathy of undetermined significance (MGUS). However, to date, no studies have evaluated whether changes in BMI over time affect the progression of MGUS to MM. We aimed to assess the association between changes in BMI following a diagnosis of MGUS and the progression of MGUS. Methods: Patients with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing (NLP) based algorithm to confirm MGUS diagnosis and progression, including smoldering MM and MM. Only patients with IgG, IgA, or light chain MGUS and black and white patients were included in the analyses. Patients with Diabetes Mellitus (DM) were excluded from analysis due to potential confounding bias. Patients who progressed within 5 years of MGUS diagnosis were also excluded. Excess BMI was defined as BMI over 25 kg/m2. To capture the trajectory of excess BMI, the area under the curve (AUC) of excess BMI during the 5 years following MGUS diagnosis was calculated. A multivariable time-to-competing-event analysis was performed to estimate the multivariable-adjusted association of AUC of excess BMI with progression with death as the competing event. The covariates included BMI at MGUS diagnosis, M-protein level (>= 1.5g/dL), age at MGUS diagnosis, sex, race, MGUS heavy chain subtype, light-chain MGUS. Results: After applying our inclusion and exclusion criteria, our analytic cohort included 7,739 MGUS patients. Our multivariable time-to-competing-event analysis revealed a positive association between excess BMI trajectory and MM progression (multivariable-adjusted hazard ratio, aHR, 1.02, 95% confidence interval, CI, 1.01-1.03) - a 2% increase in risk of progression per 1 kg/m2 increase in excess BMI per year following MGUS diagnosis. Conclusion: In patients diagnosed with MGUS, increases in excess BMI by 1 kg/m2 per year were associated with 2% increased risk of progression to MM. This finding suggests that maintaining a healthy weight in patients with MGUS may reduce the risk of progression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prevalence of Clonal Hematopoiesis in Patients with Monoclonal Gammopathy of Undetermined Significance

INTRODUCTION: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of progeny derived from hematopoietic stem cells (HSCs) that have acquired somatic mutations at a VAF greater that 2%. CHIP manifests in 10% of patients older than 65 and is associated with an increased risk of progression to hematologic malignancies such as the myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Although the risk factors for developing CHIP remain incompletely defined, they include prior exposure to chemotherapy and a history of smoking. Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the abnormal growth of clonal plasma cells in the bone marrow and carries a risk of 1% for progression to multiple myeloma (MM) per year. Like CHIP, it becomes more prevalent with age and has been associated with smoking. Additionally, patients with MM have been demonstrated to have an increased risk for myeloid malignancies. Thus, an examination for a correlation between CHIP and MGUS promises to reveal a link between these two pre-malignant conditions. However, a recent study did not demonstrate such an association, but this study was performed in a very elderly population and may not be applicable to younger patients. In this study, we aim to assess the relationship between CHIP and MGUS in a population-based cohort of MGUS patients seen at UT Southwestern Medical Center. METHODS: To evaluate an association between CHIP and MGUS, we collected bone marrow samples from 37 patients diagnosed with MGUS at UT Southwestern Medical Center. We employed a hybridization capture-based next generation sequencing assay in order to detect CHIP. We identified 24 genes known to cause CHIP in adults. We also evaluated patients' risk for developing Multiple Myeloma after having been diagnosed with CHIP. RESULTS: The mean age of MGUS patients was 68, ranging between 26-92. 17 patients had IgG, 10 had IgA, five had IgM, and five had light-chain MGUS. We identified 18 mutations to validate the presence of CHIP in 10 (27%) patients, with the most frequent being in DNMT3A and TET2 (Fig. 1). Three out of the 10 patients harbored two mutations and one patient harbored four mutations. History of chemotherapy (n=6) and smoking (n=14) was taken into consideration to determine the relative risk of patients with MGUS developing CHIP. We found that those who had a prior history of smoking and chemotherapy displayed a higher risk of acquiring CHIP (Fig. 2). 54% of patients displayed high levels of serum kappa free light chains at the time of diagnosis. CONCLUSION: There was no significant association between CHIP and MM progression. Our analysis showed one patient with CHIP progression, and two patients without CHIP progression. Because the rates of CHIP and MGUS are positively correlated with characteristics like aging and a history of smoking, we expected to see relatively high rates of CHIP in patients within our cohort. However, our data suggests that CHIP is frequent (27%) in MGUS patients, but larger future cohorts need to be evaluated to validate this association. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P878: HIGH MUTATIONAL BURDEN OF CHROMATIN MODIFYING GENES DEFINES A RELATIVELY INDOLENT SUBGROUP OF PLASMA CELL DYSCRASIAS

Background: Plasma cell dyscrasias (PCDs), including multiple myeloma (MM), light chain amyloidosis (AL), POEMS syndrome, and MGUS, present different clinical features. But as malignancies of plasma cells, they potentially have common mutational patterns associated with chemotherapy and prognosis, which haven’t been elucidated. Aims: We aimed to reveal the clinically relevant subgroups of MM, AL, POEMS, and MGUS defined by mutational patterns of bone marrow plasma cells (BMPCs). Methods: We conducted targeted gene sequencing including 370 genes of BMPCs from patients with MM (n=163), AL (n=121), POEMS (n=67) and MGUS (n=13). All the subjects provided informed consent. Results: Principal component analysis of the top 100 variable genes revealed 2 major subgroups among patients with PCDs (Fig. 1a). Approximately 25% of MM, AL, POEMS and MGUS, subgroup 1 was featured by the heavily mutated genes enriched in histone modifications and chromatin organization, such as KMT2D, EP400, RUNX1, SOX9, KDM5A, NCOR2, and ARID1B. Subgroup2 showed lower total mutational burden and was featured by mutations of proto-oncogene and B cell differentiation-associated genes, such as NCOR1, APOBEC4, KRAS, TP53, FGFR3, FAM46C, and MYC (Fig. 1b). The high mutational burden of chromatin-modifying genes was exclusively observed in subgroup 1 and was comparable among MM, AL, POEMS, and MGUS (Fig. 1c). Patients in subgroup 1 showed worse responses to the first-line CyBorD for MM and AL (Fig. 1d), but better responses to the lenalidomide-based VRD for MM and Rd for POEMS. Overall, patients in subgroup 1 demonstrated longer progression-free survival (PFS), which was observed in MM, AL (Mayo12, Stage I, II), and POEMS, respectively (Fig. 1e). Image:Summary/Conclusion: These results provide mechanistic insights into a relatively indolent subgroup among patients with MM, AL, POEMS, and MGUS, which is featured by a high mutational burden of chromatin-modifying genes. This subgroup can be identified by detecting the mutations of chromatin-modifying genes in clinical management. Overall longer PFS and better response to lenalidomide-based first-line therapy can be expected.

Defining New Reference Intervals for Serum Free Light Chains in Individuals with Reduced Kidney Function: Results of the Population- Based on Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) Study

Background: In addition to serum protein electrophoresis (SPEP) and serum immunofixation (IFE), measurement of serum free light chains (FLC) has become the hallmark for detection, prognostication, and monitoring of monoclonal gammopathies. However, serum FLC levels are heavily dependent on kidney function due to discrepancy in the rate of kidney clearance of the FLC. As chronic kidney disease (CKD) is common in the general population, it is possible that a large number of individuals have false FLC results. A kidney reference interval (eGFR < 60) has previously been published based on small numers (N=688) for serum FLC ratio (0.37-3.10) instead of the standard reference interval (0.26-1.65), but no kidney reference exists for kappa (3.3-19.4mg/L) or lambda (5.7-26.3mg/L). The aim of this study was to define and improve the reference interval for individuals with various degree of decreased kidney function and assess its effect on prevalence of light chain monoclonal gammopathy of undetermined significance (LC-MGUS) among CKD patients.Methods: A total of 80,759 participants of the Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM) study were included. Participants were screened by SPEP and IFE as well as by serum FLC assay (Freelite®). Serum creatinine (SCr) value closest to the time of screening was used to calculate (CKD-EPI) eGFR. Participants with M-protein, eGFR >60 mL/min/1.73 m2, missing SCr measurements or more than 1 year from the SCr measurement to the iStopMM screening were excluded. Correlation was assessed graphically and using the Spearman correlation coefficient. A nonparametric bootstrapping method was used to calculate the 95% CI. Partitioning was determined based on the proportion of subgroups (sex, age, eGFR) outside the whole group reference interval (<0.9% or >4.1%). However, intervals were not partitioned if subgroups included few participants and/or if deemed more applicable and reasonable for clinical practice. LC-MGUS was defined as FLC ratio outside the reference interval and raised FLC level without evidence of monoclonal heavy chain on SPEP or IFE or end-organ damage attributed to the plasma cell proliferative disorder.Results: Of 75,422 individuals who were screened, 6,503 (12%) participants had eGFR < 60 mL/min/1.73 m2, without evidence of monoclonality on SPEP or IFE and were analysed further. The median (IQR) kappa level was 21.7 (16.6-29.4) mg/L, lambda level 19.0 mg/L (14.8-25.0) and FLC ratio 1.16 (0.97-1.39). Serum FLC levels increased with decreasing eGFR: serum free kappa (ρ= -0.44, p < 0.001), lambda (ρ= -0.39, p < 0.001), and FLC ratio (ρ= -0.15, p < 0.001). Using current reference intervals, 60% and 21% of persons had values outside the normal range for kappa and lambda, respectively. The FLC ratio was outside the standard reference interval in 9% and outside the kidney reference interval in 0.6% of participants. Based on these findings, we established new reference intervals for FLC and FLC ratio (Table). Participants on dialysis (N=26) had significantly higher median (IQR) serum free kappa 29.3 mg/L (26.1-57.6, p = 0.01) and lambda 25.1 mg/L (19.5-52.6, p = 0.01) than participants with eGFR 30-59, but no significant difference compared to participants with eGFR < 30 (p = 0.57). The FLC ratio in participants on dialysis was 1.22 (0.96-1.37), which was similar to participants with eGFR 45-59 (p = 0.63) and 30-44 (p = 0.34). Participants on dialysis had significantly lower FLC ratio than participants with eGFR < 30, or 1.31 (1.10-1.57, p = 0.02). Utilising our novel reference intervals, the crude prevalence of LC-MGUS in all participants with eGFR < 60 was 75 (1.2%), with no difference between participants with eGFR of 45-59, 30-44 and < 30, respectively. When the crude rate of LC-MGUS was compared to a rate based on previous reference intervals, the crude rate of both kappa and lambda LC-MGUS increased in participants with eGFR 45-59, eGFR 30-44 and eGFR < 30 (p<0.001).Conclusion: Current reference intervals for serum FLC and FLC ratio are inaccurate for patients with decreased kidney function. Here we propose new reference intervals for serum FLC and FLC ratio for use in patients with CKD which also seem to be accurate in patients on dialysis. Implementing these novel reference intervals is likely to increase the sensitivity and specificity of the analyses and lead to a more accurate diagnosis of monoclonal gammopathy in individuals with kidney dysfunction. [Display omitted] DisclosuresKampanis: The Binding Site: Current Employment. Hultcrantz: Intellisphere LLC: Consultancy; Curio Science LLC: Consultancy; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Daiichi Sankyo: Research Funding. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Research Funding; Amgen: Honoraria; Janssen: Honoraria; Celgene: Research Funding; Janssen: Other: IDMC; Takeda: Other: IDMC; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

Estimating Selection Bias in Previous Monoclonal Gammopathy of Undetermined Significance Research - the Importance of Screening: Results from the Population-Based Screening Study Iceland Screens, Treats or Prevents Multiple Myeloma (iStopMM)

IntroductionMonoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder preceding multiple myeloma and related disorders, present in 4.2% of the population over the age of 50. Although usually asymptomatic, MGUS has been associated with various health-related problems, including thrombosis, infections, fractures, neuropathy, and death. Because MGUS is asymptomatic, its diagnosis is typically incidental, during clinical workup for unrelated medical issues, and therefore most individuals remain undiagnosed. Consequently, MGUS cohorts in past studies may have suffered from more comorbidities than the actual population with MGUS. This might have introduced selection bias in previous studies on MGUS, which extent has not been studied in a systematic way. Therefore, previously reported associations between MGUS and various medical issues might not be as profound as formerly observed. The aim of this study was to compare characteristics of incidentally diagnosed MGUS versus MGUS diagnosed by systematic screening, with particular focus on demographics, comorbidities, and MGUS-related factors.MethodsThe study is based on the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study. iStopMM is a population-based screening study for MGUS and a randomized controlled trial of follow-up strategies that has included 54% (n = 80,759) of the Icelandic population above 40 years of age. In total, 75,422 participants were screened for MGUS by serum protein electrophoresis (SPEP) and free light chain (FLC) assay. Information on which individuals had incidentally diagnosed MGUS (clinical MGUS) prior to participation in iStopMM were gathered from the Icelandic cancer registry and laboratory results from Landspítali University Hospital and Læknasetrið, the only laboratories in Iceland that perform SPEP. M-protein concentration, MGUS isotype and FLC ratio were obtained from the original screening samples. Comorbidity data was acquired from two high-quality national registries: Hospital Discharge Register and Register of Primary Health Care Contacts, with >95% completeness and accuracy. MGUS diagnosed by screening was further classified into MGUS with or without M-proteins (light-chain MGUS). Those with clinical MGUS were used as the reference group in all analyses. Since all individuals with clinical MGUS had M-proteins, individuals with light-chain MGUS were excluded from this study. T-test and chi-square test were used for demographic comparison; linear regression adjusting for sex and age for continuous variables, and logistic regression adjusting for sex and age for comparison of categorical variables, regarding MGUS-related factors and comorbidities.ResultsThe study cohort consisted of 3,300 individuals who had MGUS with M-proteins; 224 individuals with clinical MGUS and 3,076 with screened MGUS. The clinical MGUS group was significantly older (p <0.01), more likely to live in the capital area of Iceland (p 0.02), and had a 0.14 g/dL higher mean M-protein concentration (95% confidence interval [95% CI] 0.10-0.19 g/dL, p <0.001) than those with screened MGUS. Individuals with clinical MGUS were also 1.73 times more likely to have a comorbidity (odds ratio [OR] 1.73, 95% CI 1.14-2.72, p 0.01) than those with screened MGUS, reflected in a significantly higher mean number of comorbidities (2.79 vs. 2.09, p <0.001). Finally, clinical MGUS were significantly more likely to have arrhythmias (OR 1.45, p 0.05), chronic kidney diseases (OR 2.42, p <0.001), endocrine diseases (OR 1.82, p <0.001), heart failure (OR 2.60, p <0.001), neurological diseases (OR 3.07, p <0.001) or rheumatological diseases (OR 3.25, p <0.001).DiscussionIn this large population-based study including 75,000 screened individuals, we found clinical MGUS cases to be older, more likely to live in Iceland's capital area, and have a higher M-protein concentration than those found to have MGUS while screened on the iStopMM study. Individuals with clinical MGUS also had a higher number of underlying comorbidities and were 1.5-3.3 times more likely to suffer from arrhythmias, chronic kidney diseases, endocrine disorders, heart failure, neurological diseases, and rheumatological diseases. Our findings highlight the importance of screening studies to evaluate the true epidemiological and biological implications of MGUS and suggest selection bias in prior studies. [Display omitted] DisclosuresKampanis: The Binding Site: Current Employment. Hultcrantz: Daiichi Sankyo: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Amgen: Research Funding; Intellisphere LLC: Consultancy. Durie: Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy; Amgen: Other: fees from non-CME/CE services . Harding: The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landgren: Janssen: Honoraria; Janssen: Other: IDMC; Takeda: Other: IDMC; Janssen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Amgen: Research Funding; GSK: Honoraria. Kristinsson: Amgen: Research Funding; Celgene: Research Funding.

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.

High Prevalence of Monoclonal Gammopathy in a Population at Risk: The First Results of the Promise Study

High Prevalence of Monoclonal Gammopathy in a Population at Risk: The First Results of the Promise Study