Association Between Autoimmune Diseases and Monoclonal Gammopathy of Undetermined Significance : An Analysis From a Population-Based Screening Study.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a precursor of multiple myeloma (MM) and related conditions. In previous registry-based, retrospective studies, autoimmune diseases have been associated with MGUS. However, these studies were not based on a screened population and are therefore prone to ascertainment bias. OBJECTIVE: To examine whether MGUS is associated with autoimmune diseases. DESIGN: A cross-sectional study within iStopMM (Iceland Screens, Treats, or Prevents MM), a prospective, population-based screening study of MGUS. SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 75 422 persons screened for MGUS. MEASUREMENTS: Poisson regression for prevalence ratios (PRs) of MGUS among persons with or without an autoimmune disease, adjusted for age and sex. RESULTS: A total of 10 818 participants had an autoimmune disorder, of whom 599 had MGUS (61 with a prior clinical diagnosis and 538 diagnosed at study screening or evaluation). A diagnosis of an autoimmune disease was not associated with MGUS (PR, 1.05 [95% CI, 0.97 to 1.15]). However, autoimmune disease diagnoses were associated with a prior clinical diagnosis of MGUS (PR, 2.11 [CI, 1.64 to 2.70]). LIMITATION: Registry data were used to gather information on autoimmune diseases, and the homogeneity of the Icelandic population may limit the generalizability of these results. CONCLUSION: The study did not find an association between autoimmune disease and MGUS in a systematically screened population. Previous studies not done in systematically screened populations have likely been subject to ascertainment bias. The findings indicate that recommendations to routinely screen patients with autoimmune disease for MGUS may not be warranted. PRIMARY FUNDING SOURCE: The International Myeloma Foundation and the European Research Council.

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.

BACKGROUND: 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. OBJECTIVE: 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. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: 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. RESULTS: 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. LIMITATION: The prediction model will require external validation. CONCLUSION: 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. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

Nationwide implementation of lenalidomide maintenance in multiple myeloma: A retrospective, real-world study.

Lenalidomide maintenance (LM) has shown benefit in progression-free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved and publicly funded for all patients treated with HDM-ASCT since June 2019. Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of 364 MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. In a 6-month landmark analysis, early discontinuation did not negatively impact PFS or OS. The LM cohort had similar PFS, and OS compared to the pre-LM cohort. The 3-year PFS and OS rates in the LM cohort were 61% and 86%, respectively, while the pre-LM cohort had a 3-year PFS of 55% and a 3-year OS of 89%. In conclusion, the introduction of LM as a nationwide treatment option in Denmark did not lead to improved clinical outcomes.

Screening in Multiple Myeloma and Its Precursors: Are We There Yet?

BACKGROUND: Multiple myeloma (MM) is a hematological malignancy that develops over years from the asymptomatic precursors, monoclonal gammopathy of undetermined significance, and smoldering multiple myeloma. Recent evidence shows that by initiating treatment at an asymptomatic stage, outcomes in MM can be significantly improved. However, a vast majority of MM patients are diagnosed after the development of symptomatic end-organ damage and cannot reap the benefits of early treatment. The precursors of MM are easily detected by serum protein electrophoresis and free light chain assay of the serum, raising the question of whether population-based screening could detect MM at an asymptomatic stage and significantly expand the availability of early treatment in MM. Screening is a hallmark of care in many malignancies, and there are accepted criteria for when screening is appropriate. CONTENT: Here we review the available relevant evidence for the introduction of screening and discuss whether screening for MM and its precursors fulfills these criteria. We also highlight gaps in our current knowledge, most notably a lack of data on the benefits and harms of screening and the lack of a defined target population. There are ongoing studies that may fill these critical gaps in the literature, but their results are still pending. SUMMARY: Screening could lead to a paradigm shift in the care of patients with MM, but critical scientific questions need to be answered before screening of healthy individuals can be recommended. In short, we should not screen for MM and its precursors-yet.

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.

Determining hemodilution in diagnostic bone marrow aspirated samples in plasma cell disorders by next-generation flow cytometry: Proposal for a bone marrow quality index.

Hemodilution of bone marrow (BM) aspirates is a limitation of multiparameter flow cytometry (MFC) in plasma cell disorders. There is a need for a validated approach for assessing sample quality and the distribution of non-plasma cell BM populations by MFC could provide a solution. We evaluated BM-associated cell populations, assessed by next-generation flow cytometry (NGF) and white blood cell (WBC) count in 351 BM aspirated samples from 219 participants with plasma cell disorders in the Iceland Screens, Treats, or Prevents MM study (iStopMM), as markers of hemodilution by their discriminatory ability between first and (generally more hemodiluted) second pull BM aspirated samples. The most discriminating markers were used to derive a novel BM quality index (BMQI). Nucleated red blood cells and myeloid precursors provided the greatest discriminatory ability between first vs second pull samples (area under the curve (AUC): 0.87 and 0.85, respectively), significantly better than B cell precursors (AUC = 0.64; p < 0.001), mast cells (AUC = 0.65; p < 0.001), and the BM WBC count (AUC = 0.77; p < 0.05). We generated a novel BMQI that is intrinsic to current NGF protocols, for evaluating quality of diagnostic BM samples and suggest the use of a BMQI scoring system for interpreting results and guiding appropriate actions.

Immunophenotypic assessment of clonal plasma cells and B-cells in bone marrow and blood in the diagnostic classification of early stage monoclonal gammopathies: an iSTOPMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is the earliest discernible stage of multiple myeloma (MM) and Waldenström's macroglobulinemia (WM). Early diagnosis of MG may be compromised by the low-level infiltration, undetectable to low-sensitive methodologies. Here, we investigated the prevalence and immunophenotypic profile of clonal (c) plasma cells (PC) and/or cB-lymphocytes in bone marrow (BM) and blood of subjects with a serum M-component from the iSTOPMM program, using high-sensitive next-generation flow cytometry (NGF), and its utility in the diagnostic classification of early-stage MG. We studied 164 paired BM and blood samples from 82 subjects, focusing the analysis on: 55 MGUS, 12 smoldering MM (SMM) and 8 smoldering WM (SWM). cPC were detected in 84% of the BM samples and cB-lymphocytes in 45%, coexisting in 39% of cases. In 29% of patients, the phenotypic features of cPC and/or cB-lymphocytes allowed a more accurate disease classification, including: 19/55 (35%) MGUS, 1/12 (8%) SMM and 2/8 (25%) SWM. Blood samples were informative in 49% of the BM-positive cases. We demonstrated the utility of NGF for a more accurate diagnostic classification of early-stage MG.

Changes in Anxiety following Taste Education Intervention: Fussy Eating Children with and without Neurodevelopmental Disorders.

Despite the surge in studies on fussy eating in recent years, anxiety as an associated factor is generally not considered, even though children with fussy eating and those with neurodevelopmental disorders, including Autism Spectrum Disorder or Attention Deficit/Hyperactivity Disorder (ADHD) often have higher levels of anxiety than typically developing children. The current study investigated changes in anxiety scores during a Taste Education intervention, a seven-week school-based intervention for 71 children with fussy eating. Comparisons were made based on neurodevelopmental status (between children with (n = 30) and without (n = 41) neurodevelopmental disorders). Participants were paired based on age, sex, and neurodevelopmental disorder. The Multidimensional Anxiety Scale for Children (MASC) was administered at delayed intervention (for those waiting 7 weeks before starting the intervention), pre-intervention, post-intervention, and at six-month follow-up. Results did not indicate elevated anxiety based on mean MASC T-scores. MASC Total T-scores ranged from slightly elevated to average, decreasing significantly between pre-intervention and post-intervention, plateauing at six-month follow-up. Significant reductions between measurement points were seen for the physical symptoms, social anxiety, and separation anxiety subscales, but not for harm avoidance. Repeated measures analysis of variance with neurodevelopmental disorders as between-subjects factors did not reveal a significant interaction effect between neurodevelopmental disorders and changes in MASC Total score or subscales. The results indicated that our food-based intervention did not elevate MASC scores in fussy eating children, with or without neurodevelopmental disorders.

Disease associations with monoclonal gammopathy of undetermined significance can only be evaluated using screened cohorts: results from the population-based iStopMM study.

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition that precedes multiple myeloma and related disorders but has also been associated with other medical conditions. Since systematic screening is not recommended, MGUS is typically diagnosed due to underlying diseases and most cases are not diagnosed. Most previous studies on MGUS disease associations have been based on clinical cohorts, possibly resulting in selection bias. Here we estimate this selection bias by comparing clinically diagnosed and screened individuals with MGUS with regards to demographics, laboratory features, and comorbidities. A total of 75,422 participants in the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study were screened for MGUS by serum protein electrophoresis, immunofixation and free light chain assay (clinicaltrials gov. Identifier: NCT03327597). We identified 3,352 individuals with MGUS, whereof 240 had previously been clinically diagnosed (clinical MGUS), and crosslinked our data with large, nationwide registries for information on comorbidities. Those with clinical MGUS were more likely to have at least one comorbidity (odds ratio=2.24; 95% confidence interval: 1.30-4.19), and on average had more comorbidities than the screened MGUS group (3.23 vs. 2.36, mean difference 0.68; 95% confidence interval: 0.46-0.90). They were also more likely to have rheumatological disease, neurological disease, chronic kidney disease, liver disease, heart failure, or endocrine disorders. These findings indicate that individuals with clinical MGUS have more comorbidities than the general MGUS population and that previous studies have been affected by significant selection bias. Our findings highlight the importance of screening data when studying biological and epidemiological implications of MGUS.

Body Composition in Fussy-Eating Children, with and without Neurodevelopmental Disorders, and Their Parents, Following a Taste Education Intervention.

Fussy eaters may have an increased risk of becoming overweight or obese as adolescents, with fussy eating and weight status also correlating with neurodevelopmental disorders (NDs) such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Further, maternal and children's weight status relationships are well-established. In this study, we analyzed the body composition of parent-child dyads using bioelectrical impedance analysis (BIA). Fifty-one children aged 8-12 years, with an ND (n = 18) and without (n = 33), and their parents, participated in a 7-week food-based Taste Education intervention with 6-month follow-up. The paired t-test was used to compare differences in body composition based on children's ND status. In logistic regression analysis, odds of children being in the overweight/obese or overfat/obese categories increased by a factor of 9.1 and 10.6, respectively, when having NDs, adjusting for parents' BMI (body mass index) or fat percentage (FAT%). Children with NDs and their parents had significantly higher mean BMI-SDS (BMI standard deviation score) and FAT% at pre-intervention than children without NDs and their parents. Mean BMI-SDS and FAT% lowered significantly between time points for children with NDs and their parents but not for children without NDs or their parents. The findings underline the need for additional exploration into the relationships between children's and parents' body composition based on children's ND status.

Prevalence of smoldering multiple myeloma based on nationwide screening.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma. Here we define the epidemiological characteristics of SMM in the general population in Iceland. The iStopMM study (ClinicalTrials.gov ID: NCT03327597 ) is a nationwide screening study for multiple myeloma precursors where all residents in Iceland 40 years or older were invited to participate. SMM was defined as 10-60% bone marrow plasma cells and/or monoclonal (M) protein concentration ≥3 g dl-1, in the absence of myeloma-defining events. Of the 80,759 who gave informed consent to participate, 75,422 (93%) were screened. The prevalence of SMM in the total population was 0.53% (95% confidence interval (CI) = 0.49-0.57%) in individuals 40 years or older. In men and women, the prevalence of SMM was 0.67% (95% CI = 0.62-0.73%) and 0.39% (95% CI = 0.35-0.43%), respectively; it increased with age in both sexes. For the 193 individuals with SMM, median age was 70 years (range 44-92 years) and 60% were males. The mean M protein concentration of individuals with SMM was 0.62 g dl-1 (range 0.01-3.5 g dl-1) and 73% had 11-20% bone marrow plasma cell infiltration. The high prevalence of SMM has implications for future treatment policies in multiple myeloma as the evidence supporting treatment initiation at the SMM stage is emerging.

The consultant's guide to smoldering multiple myeloma.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM). The prevalence of SMM is 0.5% in persons over 40 years old; it is higher in men than women and increases with age. When SMM is diagnosed, a thorough diagnostic workup is necessary to exclude myeloma-defining events and stratify patients according to risk of progression to MM. While close monitoring for progression remains the best management for most patients with SMM, in this article, we discuss if treatment initiation before myeloma-defining events occur might be relevant in selected high-risk cases. Two randomized clinical trials have shown a clinical benefit of initiating treatment at the SMM stage, whereof 1 showed an overall survival benefit for those receiving treatment. We discuss various risk stratification models in SMM, important treatment trials, and ongoing trials. Finally, we present how to approach the clinical management of patients with SMM.

Changes in Eating Behaviors Following Taste Education Intervention: Focusing on Children with and without Neurodevelopmental Disorders and Their Families: A Randomized Controlled Trial.

Fussy-eating children often display problematic behaviors around mealtimes, such as irritation, opposition, or may even throw tantrums. This may lead to reduced food variety and poor nutritional profiles, which may increase parents' worries about their children's diet, particularly when the children also have neurodevelopmental disorders (ND) such as Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactive Disorder (ADHD). To investigate the effect of Taste Education on problematic mealtime behaviors, 81 children aged 8-12 years, with ND (n = 33) and without (n = 48), and their parents, participated in a 7-week Taste Education intervention. Children were matched on age, sex, and ND, and allocated at random into Immediate-intervention and Delayed-intervention groups. Parents completed the Meals in Our Household Questionnaire (MiOH). To examine changes in MiOH-scores, repeated-measures analysis-of-variance with time-points were used, with condition as factors (Immediate intervention and Delayed intervention). Baseline measures were adjusted for, and a robust linear mixed-model was fitted. Results showed superior outcomes for Intervention compared to waiting on all measures of MiOH, with stable effects through six-month follow-up. Differences were non-significant between children with and without ND. The Taste Education program suggests a promising, simple, and non-intrusive way to reduce children's problematic mealtime behaviors in the long term.

Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study.

Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26-1.65) in 9% of participants and outside current kidney reference interval (0.37-3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46-2.62, 0.48-3.38, and 0.54-3.30 for eGFR 45-59, 30-44, and < 30 mL/min/1.73 m2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.

Monoclonal gammopathy of undetermined significance and COVID-19: a population-based cohort study.

Multiple myeloma (MM) patients have increased risk of severe coronavirus disease 2019 (COVID-19) when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM has been associated with immune dysfunction which may lead to severe COVID-19. No systematic data have been published on COVID-19 in individuals with MGUS. We conducted a large population-based cohort study evaluating the risk of SARS-CoV-2 infection and severe COVID-19 among individuals with MGUS. We included 75,422 Icelanders born before 1976, who had been screened for MGUS in the Iceland Screens Treats or Prevents Multiple Myeloma study (iStopMM). Data on SARS-CoV-2 testing and COVID-19 severity were acquired from the Icelandic COVID-19 Study Group. Using a test-negative study design, we included 32,047 iStopMM participants who had been tested for SARS-CoV-2, of whom 1754 had MGUS. Among these participants, 1100 participants, tested positive, 65 of whom had MGUS. Severe COVID-19 developed in 230 participants, including 16 with MGUS. MGUS was not associated with SARS-CoV-2 infection (Odds ratio (OR): 1.05; 95% confidence interval (CI): 0.81-1.36; p = 0.72) or severe COVID-19 (OR: 0.99; 95%CI: 0.52-1.91; p = 0.99). These findings indicate that MGUS does not affect the susceptibility to SARS-CoV-2 or the severity of COVID-19.

Taste education - A food-based intervention in a school setting, focusing on children with and without neurodevelopmental disorders and their families. A randomized controlled trial.

Children with neurodevelopmental disorders (ND) such as Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactive Disorder (ADHD) have high levels of fussy eating. However, no school-based food interventions exist for children with ASD and ADHD. To investigate the effect of Taste Education, 81 children with ND (n = 33), and without (n = 48), aged 8-12 years, and their parents, participated in a 7-week food intervention. Children were matched on age, ND, and sex, and randomized into Immediate-intervention and Delayed-intervention groups. Parents completed the Children's Eating Behaviour Questionnaire (CEBQ), and a food-variety questionnaire. After adjusting for baseline measures, repeated-measures analysis-of-variance with time-points, and condition as factors (Immediate intervention and Delayed intervention) were used to examine changes in CEBQ-scores, with a robust linear mixed-model fitted. Changes in percentage of accepted foods were tested using a logistic-regression model adjusting for baseline acceptance. Results showed superior results for Intervention compared to waiting, on Food fussiness, but not Enjoyment of food, with stable effects through six-months follow-up. There were non-significant differences between children with and without ND. Results also showed increased odds of accepting vegetables by a factor of 1.6 (95% Confidence Interval [CI]: 1.33-1.93, p < .001); nuts and seeds by a factor of 1.4 (95% CI: 1.27-1.6, p < .001), but no significant association for fruit (OR 1.12, 95% CI: 0.92-1.34, p = .244). Trends were similar for children regardless of ND-status. The Taste Education program, shows promise, as a simple, non-invasive way to decrease fussy eating and increase food variety in the long-term.

Iceland screens, treats, or prevents multiple myeloma (iStopMM): a population-based screening study for monoclonal gammopathy of undetermined significance and randomized controlled trial of follow-up strategies.

Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Population-based screening for MGUS could identify candidates for early treatment in MM. Here we describe the Iceland Screens, Treats, or Prevents Multiple Myeloma study (iStopMM), the first population-based screening study for MGUS including a randomized trial of follow-up strategies. Icelandic residents born before 1976 were offered participation. Blood samples are collected alongside blood sampling in the Icelandic healthcare system. Participants with MGUS are randomized to three study arms. Arm 1 is not contacted, arm 2 follows current guidelines, and arm 3 follows a more intensive strategy. Participants who progress are offered early treatment. Samples are collected longitudinally from arms 2 and 3 for the study biobank. All participants repeatedly answer questionnaires on various exposures and outcomes including quality of life and psychiatric health. National registries on health are cross-linked to all participants. Of the 148,704 individuals in the target population, 80 759 (54.3%) provided informed consent for participation. With a very high participation rate, the data from the iStopMM study will answer important questions on MGUS, including potentials harms and benefits of screening. The study can lead to a paradigm shift in MM therapy towards screening and early therapy.

Untangling fracture risk in monoclonal gammopathy of undetermined significance: A population-based cohort study.

OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is the asymptomatic precursor of multiple myeloma (MM). Lytic bone lesions and fractures are hallmarks of MM and although there are no lytic lesions in MGUS, it has also been associated with fractures. The causes of fractures in MGUS are currently unclear but potential causes include inherent MGUS bone disease, undiagnosed MM, and peripheral neuropathy (PN). We therefore conducted a large population-based study including 8395 individuals with MGUS and 30 851 matched controls from Sweden. METHODS: Data on fractures, PN, and confounders were acquired from high-quality registers in Sweden. RESULTS: Monoclonal gammopathy of undetermined significance and PN were independently associated with fractures (hazard ratio [HR]: 1.29; 95% confidence interval [95% CI]: 1.21-1.37; P < .001 and HR: 1.34; 95% CI: 1.16-1.55; P < .001). Imminent MGUS progression increased the risk of fractures (odds ratio: 1.66; 95% CI: 1.27-2.16; P < .001). Fractures were not associated with long-term risk of MGUS progression (HR: 1.08; 95% CI: 0.77-1.53; P = .64). DISCUSSION: Based on these findings, we speculate that MGUS leads to fractures through at least 3 independent mechanisms: undetected MGUS progression to MM, MGUS inherent bone disease, and PN through falls. These findings highlight the need for further study of MGUS inherent bone disease and can inform further research into fracture prevention in MGUS.