Monoclonal Gammopathy Of Undetermined Significance Cases Research Articles

Outcomes of Septuagenarians and Octogenarians with Monoclonal Gammopathy of Undetermined Significance Admitted for Acute Pulmonary Embolism

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is clinically defined with a serum monoclonal immunoglobulin of less than 3 g/dL and the presence of less than 10% of plasma cells in the bone marrow, in the absence of any end-organ damage that is typically seen in patients with multiple myeloma. The incidence of MGUS mostly involves the elderly, with a median age estimated at 70 years. While some studies have linked MGUS with a hypercoagulable state, there are no large studies investigating the impact and outcomes of MGUS in the elderly with pulmonary embolism(PE). We thus propose a national analysis to investigate. Methods: Our retrospective study via the National Inpatient Sample (NIS) focused on adults admitted with a primary diagnosis of Acute Pulmonary Embolism. We excluded all cases of ages <70 years and >90 years. Patient characteristics in acute PE cases with and without MGUS such as age, sex, race, and presence of various comorbidities such as diabetes, hypertension, obesity, among many, were explored via Chi-Square tests, t-tests, and Mann-Whitney U tests as appropriate. Differences in outcomes for PE in MGUS and non-MGUS patients were estimated via logistic regression models on SPSS 29.0. A p-value of <0.05 was considered as statistically significant. To comply with the database provider's (HCUP) guidelines, we did not report values <11. Results: Among the 327090 septuagenarians and octogenarians admitted primarily for acute PE in our study, there were 1095 (0.3%) patients with a diagnosis for MGUS that also reported a higher mean Charlson Comorbidity Index (CCI) score (4.26 vs. 2.90, p<0.01) (Table 1). While 51.1% of MGUS cases with acute PE were males, the non-MGUS group mainly consisted of females (56.1%, p<0.01). Medicare covered 91.3% and 90.8% of all MGUS and non-MGUS cases in our study, and 68.9% and 66.3% of all admissions involved Urban-teaching centers, respectively. Around 11.0% of MGUS cases also had a history of prior pulmonary embolism, while it was 8.0% in the non-MGUS cohort (p<0.01). The MGUS cohort also showed a lower prevalence of hypertension (41.1% vs.46.7%, p<0.01) while having a higher prevalence of peripheral vascular disease (11.4% vs. 5.1%, p<0.01), smoking status (40.6% vs. 37.8%, p=0.049), lipid disorders (56.6% vs. 50.6%, p<0.01), and chronic kidney disease (35.6% vs. 20.0%, p<0.01) than the non-MGUS group. MGUS patients showed lower odds of experiencing in-patient events such as myocardial infarction (aOR 0.345, 95% CI 0.221-0.538, p<0.01), acute kidney injury (aOR 0.843, 95% CI 0.719-0.990, p=0.037), and respiratory compromise (aOR 0.749, 95% CI 0.652-0.860, p<0.01). While a higher odds of cardiogenic shock (aOR 1.903, 95% CI 1.316-2.753, p<0.01) was also noted, patients with and without MGUS had no differences related to in-hospital mortality (aOR0.721, 95% CI 0.513-1.013, p=0.060) or the need for IVC filters (aOR 1.156, 95% CI 0.924-1.446, p=0.206). MGUS patients also experienced a longer stay (mean length of stay 4.91 vs. 4.62 days, p<0.01). Conclusion: This nationwide data analysis suggests a higher prevalence of a history of previous PE in MGUS cases admitted for PE than those without MGUS. Furthermore, while odds of events involving in-patient myocardial infarction, acute kidney injury, or respiratory compromise in MGUS patients were lower, they had a higher risk of cardiogenic shock. It is thus vital for physicians to be on the watch-out of such complications and provide adequate testing and care in a timely manner to improve their prognosis and outcomes.

Prevalence of Monoclonal Gammopathy of Undetermined Significance in Eswatini: A Study of an African Population

Multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance (MGUS), both occur twice as often within Black populations compared to White populations, suggesting that racial factors may influence the development of MGUS, not the progression from MGUS to malignancy. The landmark epidemiologic study that described the natural history of MGUS was conducted among 21,463 of the 28,000 residents in Olmsted County, Minnesota, a 97% White population, and found the age-standardized prevalence (including light-chain, LC, MGUS) to be 4.2% (Dispenzieri, et al, Lancet, 2010). Although MGUS disproportionately affects Black individuals, few studies have been conducted on MGUS in Africa, and no prior study has evaluated MGUS in a Black African cohort inclusive of both sexes. Using a population-based biorepository from Eswatini, a small country in southern Africa, we further explored the racial disparities related to plasma cell dyscrasias. Our primary objective was to determine the prevalence of MGUS in Eswatini, as compared to that found in Olmsted County. Additionally, we aimed to determine the association between MGUS and HIV status. From 2016 to 2017, over 15,000 individuals from a nationally representative selection of households participated in the Second Eswatini Population-based HIV Impact Assessment survey, SHIMS2 (phia.icap.columbia.edu/countries/eswatini). After providing informed consent, interviews were conducted and blood samples were collected. Samples were tested for HIV, and if positive, also for CD4+ cell counts and the serologic presence of antiretroviral therapy (ART). The remaining plasma aliquots were stored and linked to their de-identified corresponding survey data for future research endeavors. For our current study, all adults over the age of 35 years who had SHIMS2 specimens stored were included in the sampling frame. We randomly selected 515 plasma samples from the sampling frame, with the sample size determined to produce a two-sided 95% confidence interval (CI) with a width of 0.05 and power >80% for MGUS prevalence and comparison by HIV status. We performed protein electrophoresis with reflex immunofixation, as well as free light chain and creatinine quantification, and defined MGUS cases by the same criteria as the Olmsted County studies. If creatinine was greater than the upper limit of normal, then the renal reference range was used for free-light-chain ratios . Historical proportions and means were compared with z-tests and t-tests, respectively. To determine associations between categorical variables, odds ratios (OR) were calculated with logistic regressions or Fisher Exact tests. The study cohort (n=515) was 60% female (n=309) with a median age of 50 years (range 35-80); 199 (38.6%) were HIV-positive, of whom 82.4% (n=164) were on ART, and 8.5% (n=17) had a CD4+ cell count of <200 cells/ul. These numbers reflected the overall national estimates (Kingdom of Eswatini, SHIMS2 Final Report, 2019). The MGUS prevalence (including LC-MGUS) standardized for age and sex was 13.2% (95%CI: 10.5-16.5) (n=68), which was significantly greater than Olmsted County (RR 3.1, p<0.0001). Most (84%, n=57) MGUS cases were LC. Prevalence of non-light-chain (NLC) MGUS was 2.1% (n=11), which was similar to Olmsted County. Of the 11 participants with NLC MGUS, 4 were considered very low risk for progression to malignancy, 6 low risk, 1 intermediate risk, and 0 high risk by Mayo stratification (Rajkumar, et al., Blood, 2005). HIV status was not found to be significantly associated with MGUS (OR: 1.05, 95%CI: 0.62-1.77). However, within the HIV-positive cohort, the odds of MGUS were 69% lower among those on ART (OR: 0.31, 95%CI: 0.11-0.82) when adjusted for age, sex, and wealth quintile. Furthermore, MGUS was 2.8 times more frequent in those with untreated HIV when compared to those with treated HIV (95%CI: 1.1-7.2, p=0.031), and 2.3 times more frequent when compared to non-HIV (95%CI: 1.0-5.6, p=0.056); treated HIV was not significantly different from non-HIV (data not shown). In conclusion, the MGUS prevalence in Eswatini was more than three-fold higher than that in Olmsted County, largely due to those with LC-MGUS. The high rate of HIV in Eswatini did not explain the high prevalence of MGUS, as the majority of those with HIV were on ART and only untreated HIV was significantly associated with MGUS.

Single Cell Multi-Omic Analysis of Neoplastic Plasma Cells across the Disease Spectrum Identifies Novel Pathobiologic Mediators and Potential Therapeutic Targets in Multiple Myeloma (MM)

Background: A challenge to developing a full understanding of MM pathobiology using bulk profiling techniques is the large degree of intra-tumoral heterogeneity from minor subclones that, despite their low representation, nonetheless contribute to therapy resistance and disease progression. Moreover, our current therapies tend to be targeted against pathways common to both neoplastic and normal plasma cells (PCs), indicating a need to define novel tumor biology modifiers that could potentially serve to improve risk stratification and as therapeutic targets. Methods: To overcome these limitations, we simultaneously evaluated individual PC single-cell transcriptome and B-cell receptor variable (VDJ) sequences from freshly enriched bone marrow biopsies. These included 33 patients with precursor conditions, 17 each with newly diagnosed symptomatic or relapsed/refractory disease (RRMM), and 3 controls using the 10x Genomics platform. A total of ~320,000 PCs were analyzed, yielding median per sample cell counts of 4,626 and ~300 million total reads. Identical immunoglobulin VDJ sequences defined monoclonal PCs, while diverse VDJ sequences at low frequencies defined polyclonal cells, allowing each patient to serve as their own control. Results: The percentage of monoclonal PCs in active MM was >84%, while precursor stages were more variable (40-100% in smoldering MM; 0.3-82% in monoclonal gammopathy of undetermined significance (MGUS)). Though we could not identify monoclonal PCs in two MGUS cases, we identified them by scRNA-seq in four MGUS patients whose bone marrow showed no clonal cells by standard clinical multiparametric flow cytometry. In differential gene expression analysis where samples were grouped based on the diagnosis, 501 dysregulated genes were identified in monoclonal PCs from symptomatic MM compared to polyclonal PCs. These included genes previously identified as disease modifiers, including Hepatocyte growth factor, Lactate dehydrogenase A, Dickkopf WNT signaling pathway inhibitor 1, CD27, and Lysosomal associated membrane protein family member 5, providing validation for our approach. Next, we identified 279 genes that were commonly dysregulated in monoclonal PCs from symptomatic vs. asymptomatic MM. We also performed unsupervised hierarchical clustering of the top 1000 most variable genes and defined three diagnostic categories. Significant ontology terms characterizing these categories broadly involved antigen processing and recognition in Group 1 (enriched in precursor stages); transcription and translation control in Group 2 (enriched in active MM); and cell division and DNA metabolism in Group 3 (enriched with RRMM) ( A). We focused on dysregulated targets that: showed differential expression in monoclonal vs. polyclonal PCs; expression in most patients within a diagnostic category; a correlation with outcomes in the CoMMpassstudy; and novelty in MM. Among these were Mitotic arrest deficient 2 like 1 (MAD2L1), a component of the mitotic spindle assembly checkpoint, and Methionine adenosyltransferase 2A (MAT2A), which catalyzes the production of S-adenosylmethionine, a key methyl donor in multiple cellular processes, from methionine and ATP. Notably, MAD2L1 inhibition with M2I1, and MAT2A targeting with the allosteric inhibitor AG-270, both produced a dose- and time-dependent inhibition in cell proliferation and reduction in myeloma cell line viability. Importantly, the effects of AG-270 ( B) were associated with induction of markers of apoptosis, including Caspase cleavage, and a reduction of Histone H3 dimethylation. Moreover, they occurred at clinically relevant concentrations based on the known pharmacokinetics of this drug in Phase I testing. Conclusions: Our combined single-cell transcriptomics and VDJ sequencing allowed a greater understanding of heterogeneity among neoplastic PCs compared to each patient's own polyclonal PCs. These analyses can identify putative novel mediators of disease pathobiology that impact prognosis, and that can serve as potential new therapeutic targets using either novel agents, or drug repurposed from other therapeutic areas, setting the stage for their translation to the clinic.

The Significance of a “MGUS” Tumor Board

Our large academic medical center consists of both a main campus and several regional sites that all offer hematology/oncology services where monoclonal gammopathy cases are referred for consultation. We receive well over 100 requests annually to see cases with abnormal monoclonal proteins. The challenge was how to triage these requests, with the goal of improving patient access to main campus myeloma experts while improving patient care and timely management. We decided to schedule cases initially referred for monoclonal gammopathy of undetermined significance (MGUS) with our advanced practice providers (APPs) both in the region and at main campus. Due to the concern for varying experience managing MGUS, differences in diagnostic practice and limited guidance we developed a novel concept to have a tumor board to review MGUS cases that were initially seen by our APPs. The “MGUS” tumor board is ran by three of our main campus myeloma focused hematologists and our myeloma dedicated APRN-PhD. We meet twice a month to review cases. Over the past 2 years we reviewed 147 cases providing recommendations for further work up. Of these, 41 cases (28%) were found to have a clinically significant monoclonal protein necessitating referral to a physician at main campus. The breakdown of these cases are detailed below in T able 1. Sixteen patients (11%) were started on treatment, the other 25 (17%) remained on observation. Another aspect of the tumor board is to provide education regarding clinically significant scenarios that involve monoclonal proteins. This tumor board offers CME credit for both APPs and physicians. By developing a team of knowledgeable APPs we have shifted 72% of monoclonal gammopathy referrals to remain under the care of APPs which improved access to main campus myeloma physician experts. This allowed the myeloma team at main campus to see more second opinions, open more clinical trials and expand our cell-therapy options for patients. Our referral base has grown and we have hired more APPs in the region and two additional myeloma physicians at main campus since starting the “MGUS” tumor board. Overall, we were successful in transitioning “MGUS” referrals to our APPs, but there were higher than expected percent of patients with clinically significant monoclonal proteins. Our data shows that it is essential for there to be some standardization for reviewing and working up “MGUS” referrals. This is especially important at large centers with multiple regional locations. We recommend a tumor board style review as it allows for discussion and education of “MGUS” referrals which prove to be far more complex in many cases.

The China Monoclonal Gammopathy Screening Project in First-Degree Relatives of Patients with Multiple Myeloma (CHAPERONE) –a Multicenter Screening Study

Background and Significance: Multiple myeloma (MM) evolves from the precursor state monoclonal gammopathy of undetermined significance (MGUS). According to previous reports, the incidence of MM and its precancerous state MGUS was lower in Asian populations than in Western populations. However, with the aging of the population, we found that the incidence of MM in China has been on the rise in recent years, and the medical burden has continued to increase. Therefore, early recognition of MM and its precursor condition is even more critical. Our previous research has confirmed that monoclonal gammopathy (M-protein) screening and close follow-up of MGUS can increase the early diagnosis rate of MM and improve the prognosis of MM patients[1]. M-protein screening in healthy people at high risk for MM is a rational strategy. The risk of MM in the first-degree relatives of myeloma patients is 2-4 times that of the general population, constituting a high-risk group for MM. Although the screening of M-protein in high-risk populations has been explored in the US (the PROMISE study), little was known about the incidence, clinical features, and prognosis of MGUS in high-risk groups in China. Here, we describe the first prospective screening project to assess the potential benefits of M-protein screening and the prevalence and outcomes of MGUS in first-degree relatives of patients with multiple myeloma in the China population (NCT05965115). Study Design and Methods: The CHAPERONE study is a prospective, multicenter screening study for MGUS in first-degree relatives of MM patients, including a risk-stratified follow-up strategy(Figure). Clinical trial registry number: NCT05965115, actively recruiting. This study aims to assess the clinical significance of screening for monoclonal gammopathy in first-degree relatives of patients with multiple myeloma in China. The primary objective is to determine the prevalence and incidence rate of MGUS, the time to disease progression (TTP), and its influencing factors in first-degree relatives of MM patients in China. The secondary and exploratory study objective is to explore the clinical/genomic features, survival, and quality of life of the screened MGUS cases. The expected screening size is 10,000 healthy persons. To be eligible, participants must be over 18, with one or more first-degree relatives (including parents, children, and biological siblings) having multiple myeloma diagnosed by the International Myeloma Working Group (IMWG) Myeloma Diagnostic Criteria. Participants with a known diagnosis of plasma cell diseases, such as MGUS, smoldering myeloma (SMM), or MM, will be excluded. All eligible participants will receive M-protein screening by serum electrophoresis. Individuals with detected M-protein will undergo further diagnostic tests, including peripheral blood tests (immunofixation electrophoresis, serum free light chain, immunoglobulin quantification, blood routine, liver and kidney function, and blood calcium level) and X-ray bone assays. Patients with suspecting MM features will undergo further bone marrow surveys to ascertain the diagnosis. Patients with MGUS will be carefully assessed and stratified by the risk of progression to MM according to the IMWG MGUS consensus. Low-risk MGUS will be followed-up annually, while intermediate/high-risk MGUS will be biannual. Participants who progress to MM will be offered early treatment. Conclusions and Future Directions: One path to making MM a preventable cancer is better understanding its precursor condition (MGUS). This trial is positioned to provide epidemiology, clinical, and potential mechanistic data on MGUS at a high-risk group in China population that has yet to be thoroughly studied. Reference: [1] Li J, Wang Y, Liu P. The impact on early diagnosis and survival outcome of M-protein screening-driven diagnostic approach to multiple myeloma in China: a cohort study[J]. J Cancer, 2019, 10(20): 4807-4813.

Determination of the target of monoclonal immunoglobulins: a novel diagnostic tool for individualized MGUS therapy, and prevention and therapy of smoldering and multiple myeloma.

Subsets of patients diagnosed with a monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) or multiple myeloma (MM), present with a monoclonal immunoglobulin (Ig) specific for an infectious pathogen, including hepatitis C and B viruses (HCV, HBV), Helicobacter pylori and several Herpesviruses. Such cases are likely initiated by infection, since in the context of HCV- or HBV-infected patients, antiviral therapy can lead to the disappearance of antigenic stimulation, control of clonal plasma cells, and reduced or suppressed monoclonal Ig production. Complete remission has been obtained with anti-HCV therapy in refractory MM with a HCV-specific monoclonal Ig, and antiviral treatments significantly improved the probability of survival of MM patients infected with HCV or HBV prior to the diagnosis of MM. Monoclonal Igs may also target glucolipids, particularly glucosylsphingosine (GlcSph), and GlcSph-reducing therapy can lead to complete remission in SMM and MM patients presenting with a GlcSph-specific monoclonal Ig. The present review describes the importance of determining the target of the monoclonal Ig of MGUS, SMM and MM patients, and discusses the efficacy of target-reducing treatments in the management of MGUS, SMM and MM cases who present with a monoclonal Ig reactive against a treatable infectious pathogen or GlcSph.

Vitamin D and monoclonal gammopathy of undetermined significance (MGUS) among U.S. Black women.

Risk factors for monoclonal gammopathy of undetermined significance (MGUS), the asymptomatic precursor to multiple myeloma, are largely unknown. We hypothesized that low vitamin D levels might be associated with higher MGUS prevalence in a national cohort of U.S. Black women. We screened archived serum samples (collected 2014-2017) from 3896 randomly selected participants in the Black Women's Health Study ages 50-79 for evidence of MGUS; samples had been assayed for 25-hydroxyvitamin D [25(OH)D] shortly after blood draw. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between 25(OH)D level and MGUS status, adjusting for age, body mass index, and season of blood draw. We identified 334 MGUS cases (8.6%) in the study population. The adjusted OR comparing women with vitamin D deficiency (25(OH)D < 20 ng/mL) to those with 25(OH)D levels ≥ 30 ng/mL was 1.27 (95% CI: 0.95, 1.72). MGUS was more prevalent among Black women with vitamin D deficiency compared to those with 25(OH)D ≥ 30 ng/mL; however, the association was not statistically significant. Future prospective studies are warranted to clarify the possible association between vitamin D and MGUS.

Multimorbidity in patients with monoclonal gammopathy of undetermined significance.

Monoclonal gammopathy of undetermined significance (MGUS), a precursor to multiple myeloma, is present in over 5% of adults aged 70 and older, a population with a high prevalence of multimorbidity. MGUS is often diagnosed incidentally when patients seek care for unrelated conditions. Our study sought to examine patterns of multimorbidity among MGUS patients, as overall health may impact patient care and the prioritization of MGUS surveillance. We examined patterns of comorbidities in 429 patients diagnosed with MGUS (2007-2015) and 1287 matched controls. Twenty-seven conditions were defined at diagnosis/index date using algorithms developed by the Centers for Medicare and Medicaid Chronic Conditions Warehouse. Patterns of common comorbidities were identified individually, in dyads and triads, and compared between MGUS cases and controls. We conducted a latent class analysis to identify comorbidity patterns among cases only. We also examined comorbidity patterns among a subset of 32 MGUS cases who progressed to cancer during the study period. The most common comorbidities among both MGUS cases and controls included hypertension and hyperlipidemia. Anemia (cases: 43%; controls: 16%) and chronic kidney disease (CKD; cases: 36%; controls: 18%), and dyads and triads containing those conditions, were more common among cases. Latent class analysis identified three classes of comorbidity among MGUS cases: hypertension-hyperlipidemia plus anemia and CKD (31%); low comorbidity burden (17%); and hypertension-hyperlipidemia alone (52%). The higher prevalence among cases of anemia and CKD, which may be involved in the pathogenesis of, or surveillance for, MGUS, warrants additional investigation.

Patients with multiple myeloma and monoclonal gammopathy of undetermined significance have variably increased thrombin generation and different sensitivity to the anticoagulant effect of activated protein C

BackgroundPatients with multiple myeloma (MM) are at high risk of thrombosis especially when receiving immunomodulatory therapy. Thrombotic risk in patients with monoclonal gammopathy of undetermined significance (MGUS) may also be increased. Although activated protein C (APC) resistance has been linked to an increased risk of thrombosis in MM, little is known about how APC influences thrombotic risk in MGUS. We compared thrombin generation (TG) in MM and MGUS patients to that of healthy controls (HCs) and investigated the exogenous effect of APC on TG in these groups. MethodsHemostasis tests including factor VIII (FVIII) and von Willebrand factor (vWF) levels were measured in platelet-poor plasma in 14 untreated MM patients, 34 MGUS patients, and 30 age and sex-matched HCs. TG assay was performed with or without the addition of APC. ResultsPeak thrombin and velocity index were significantly higher in MM and MGUS patients compared to HCs, while MM patients also had elevated endogenous thrombin potential (ETP). In MGUS cases, ETP and peak thrombin values significantly correlated with FVIII and vWF levels. In the presence of APC, peak thrombin and ETP were reduced in MGUS and control plasmas whereas lagtime and time to peak were significantly prolonged. In contrast, adding APC to MM plasma had no effect on any TG parameters. ConclusionsHypercoagulability was observed in MM and even in MGUS cases with very low monoclonal protein concentration. In MM patients, APC had no effect on TG, but it attenuated TG in MGUS patients.

Abstract C013: Racial difference in risk factors for monoclonal gammopathy of undetermined significance – The premalignant stage of multiple myeloma

Abstract Background: Black race and obesity are known risk factors for type 2 diabetes mellitus (T2DM), multiple myeloma and its precursor condition – monoclonal gammopathy of undetermined significance (MGUS). Yet, little is known about what contributes to this racial difference, particularly in MGUS, and studies have inconsistently shown that T2DM may not be a risk factor for myeloma. We aimed to investigate the racial differences in risk factors for MGUS in patients with T2DM. Methods: Patients diagnosed with T2DM from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing-based algorithm to confirm MGUS diagnosis. Among them, patients of Black and White races with ≥2 BMI measurements were included. To preserve the prevalence of MGUS in the respective population, each Black patient with MGUS was matched to 27 Black patients without MGUS; and each White patient with MGUS was matched to 44 White patients without MGUS on BMI observation window. BMI observation window for each MGUS patient was defined as time from the 1st to the last BMI measurement before MGUS diagnosis. For the matched patients without MGUS, a similar length of observation window was selected along with ≥1 measurement beyond the window to ensure no loss to follow-up during the window. Each cohort was further split into the training (80%) and testing (20%) sets. Ad-hoc features for BMI in different statistics to summarize repeated measurements within the window were defined: average, variance (var), maximum (max), minimum (min), max BMI increase per month (max dBMI/m), max BMI decrease per month (min dBMI/m), and area under the dBMI curve. Ad-hoc features for other variables, HbA1c, creatinine, potassium, and glucose, were constructed in a similar fashion. To overcome the imbalanced MGUS cases (vs no MGUS), Synthetic Minority Over-Sampling Technique algorithm was used. To evaluate performance, we implemented 5-fold cross-validation using logistic regression and generated AUC score. Results: A total of 2,468 White and 3,981 Black T2DM MGUS patients were included. Logistic regression achieved an average AUC score of 0.76 (95% CI 0.72, 0.79) for Whites and 0.76 (95% CI 0.73, 0.78) for Blacks. In both races, the most significant risk factor for MGUS was max dBMI/m, followed by max BMI for Whites and var BMI for Blacks. Conversely, min glucose was the most significant factor inversely associated with the incidence of MGUS for both races. Conclusion: There is no significant difference in the most significant factors contributing to MGUS between the two races. In patients with T2DM, drastic change in body weight is the most significant risk factor for MGUS among others, while maintaining low glucose is the most protective factor for both races. Regardless of race, T2DM patients of high myeloma risk are encouraged to maintain a stable weight and low glucose level. Citation Format: Yao-Chi Yu, Mei Wang, Akhil Kumar, Kristin Vargo, Lawrence Liu, Theodore Thomas, Kristen Sanfilippo, Martin Schoen, Graham Colditz, Jr-Shin Li, Su-Hsin Chang. Racial difference in risk factors for monoclonal gammopathy of undetermined significance – The premalignant stage of multiple myeloma [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C013.

Identifying monoclonal gammopathy of undetermined significance from electronic health records.

Monoclonal gammopathy of undetermined significance (MGUS) precedes multiple myeloma (MM). Use of electronic health records may facilitate large-scale epidemiologic research to elucidate risk factors for the progression of MGUS to MM or other lymphoid malignancies. We evaluated the accuracy of an electronic health records-based approach for identifying clinically diagnosed MGUS cases for inclusion in studies of patient outcomes/ progression risk. Data were retrieved from Kaiser Permanente Southern California's comprehensive electronic health records, which contain documentation of all outpatient and inpatient visits, laboratory tests, diagnosis codes and a cancer registry. We ascertained potential MGUS cases diagnosed between 2008 and 2014 using the presence of an MGUS ICD-9 diagnosis code (273.1). We initially excluded those diagnosed with MM within 6months after MGUS diagnosis, then subsequently those with any lymphoid malignancy diagnosis from 2007 to 2014. We reviewed medical charts for 100 randomly selected potential cases for evidence of a physician diagnosis of MGUS, which served as our gold standard for case confirmation. To assess sensitivity, we also investigated the presence of the ICD-9 code in the records of 40 randomly selected and chart review-confirmed MGUS cases among patients with a laboratory report of elevated circulating monoclonal (M-) protein (a key test for MGUS diagnosis) and no subsequent lymphoid malignancy (as described above). The positive predictive value (PPV) for the ICD-9 code was 98%. All MGUS cases confirmed by chart review also had confirmatory laboratory test results. Of the confirmed cases first identified via M-protein test results, 88% also had the ICD-9 diagnosis code. The diagnosis code-based approach has excellent PPV and likely high sensitivity for detecting clinically diagnosed MGUS. The generalizability of this approach outside an integrated healthcare system warrants further evaluation.

Predictive Immune Markers for Disease Progression in Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance

Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM, are plasma cell neoplasms. The evolution of the treatment of MM in recent years has dramatically improved the outcome for these patients. Currently, multidisciplinary studies are being conducted to elucidate the etiopathogenesis of the disease and develop specific treatment agents and prognostic markers. The present study investigates the relationships between immunoexpression of CD138, Pan-Ras, CCL-3, DKK-1, and MUM-1 and disease progression in cases of MM and MGUS. Immunohistochemical staining for CD138, Pan-Ras, CCL-3, DKK-1, and MUM-1 were performed on bone marrow biopsy samples from 94 MM and 20 MGUS patients diagnosed between 2011 and 2018. Immunohistochemical results were examined semiquantitatively, and the associations between the immunohistochemical, clinical, and biochemical markers utilized for MM and MGUS patient staging were analyzed. Pan-Ras, DKK-1, and MUM-1 staining results were significantly higher in MM compared to MGUS (p=0.005, 0.001, and 0.001, respectively). The mean CCL-3 expression in patients with MGUS was 23.15%, while it was 18.68% in cases of MM (p=0.413). CCL-3 expression was significantly higher in high-risk MGUS cases compared to other risk groups according to the Mayo Clinic Risk Stratification for MGUS. According to the International Staging System and the Revised International Staging System, CD138 expression was higher among stage II and stage III patients than stage I patients. Differences in Pan-Ras, MUM-1, DKK-1, and CCL-3 expressions between MM and MGUS suggest that these molecules may play a role in the progression of MGUS to MM. CCL-3, an immunohistochemical marker, may be predictive of MGUS progression, while CD138 is associated with more advanced stages of MM.

Type 1 Cryoglobulinaemia Associated with Waldenström Macroglobulinemia, IgM MGUS or Non-Hodgkin Lymphoma

Introduction: Type 1 cryoglobulinaemia is defined by monoclonal immunoglobulins which precipitate at temperatures <37°C and redissolve on warming. IgM monoclonal protein may be associated with type I cryoglobulinaemia with underlying Waldenström macroglobulinemia (WM), non-Hodgkin lymphoma (NHL) or monoclonal gammopathy of undetermined significance (MGUS). Due to its rarity, the incidence and clinical outcomes are poorly understood, with fewer than 40 patients characterised in the largest series. Clonal characteristics have not previously been described. We analysed the incidence, clinical and clonal characteristics of the largest reported series of IgM-associated type I cryoglobulinaemia. Methods: Data for consecutive adult patients (> 18 years) with IgM-associated type I cryoglobulinaemia identified between 2013-2022 from 2 centres (University College London Hospital [UCLH], UK and AMC, Netherlands) were retrospectively analysed and followed up to June 2022. In order to calculate the incidence of type I cryoglobulinaemia, the total number of requests performed at UCLH was also determined. Results: 423 samples were screened for cryoglobulinaemia between 2013-2022 from all patients with an IgM-associated disorder at the specialist centre, UCLH. 140 (33%) were positive for all-type cryoglobulinaemia; 94 (22%) patients had type I cryoglobulinaemia. Four additional patients were recruited from Amsterdam UMC, without incidence data. In total, 98 patients (58 male, 40 female) were identified with type I cryoglobulinaemia; the majority with underlying WM (defined as >10% bone marrow infiltration) (77; 79%), and remaining IgM MGUS (16; 16%) and NHL (4 marginal zone lymphoma, 1 CLL; 5%). The median age at cryoglobulin diagnosis was 66 years (range 39-90). There was a kappa light-chain predominance in the majority (85%). MYD88L265Pwas present in 44/49 (90%) of WM and 3/8 (38%) MGUS cases. CXCR4 was mutated in 5/13 (38%) WM cases. Coexistent IgM-associated disorders were present in 25: cold agglutinin disease/syndrome (CAD/CAS, 15%), Bing-Neel syndrome (7%), anti-MAG antibodies (5%), Schnitzler syndrome (1%). Those with coexistent CAD/CAS had characteristics of a CAD clone, significantly associated with MGUS (vs WM/NHL, p<0.0001) and MYD88-wild type (p<0.0001). Patients with co-existent anti-MAG antibodies were significantly more likely to have MGUS (p=0.0245). Median M-protein at diagnosis of cryoglobulinaemia was 12g/l (range 0-63) and lowest in the MGUS cohort vs WM vs NHL (4g/l vs 16g/l vs 10g/l, p=0.0003). The majority were diagnosed with cryoglobulinaemia >3 months after diagnosis of the underlying IgM disorder (60/98; 61%), at a median of 46 months (range 4-442) and longer in those with WM compared with MGUS or NHL (51 vs 17 vs 13 months, p=0.023). Forty nine percent were symptomatic at cryoglobulinaemia diagnosis, with a trend towards a greater proportion in those with MGUS/NHL vs WM (75%/60% vs 43%, p=0.0569). The most common symptoms were cutaneous/vasomotor symptoms (28%), neuropathy (21%), hyperviscosity (10%), arthralgia (7%) and renal involvement (2%). No cases had cardiac or pulmonary involvement. At a median follow up of 2.4 years (range 0-9.4), 2-year overall survival (OS) was 89% (95% CI 80-94), 5-year OS was 73% (95% CI 56-84). Age was the only predictor of OS (Hazard ratio [HR] 1.07, 95% CI 1.01-1.12, p=0.006). Fourteen patients required chemoimmunotherapy for cryoglobulinaemia at a median of 1 month (0-7) from diagnosis for cutaneous manifestations (5/14; 36%), cryoglobulinaemic glomerulopathy (2/14; 14%) or hyperviscosity (9/14; 64%). Independent predictors of cryoglobulinaemia-indicated treatment-free survival/death included cutaneous involvement (HR 1.48, 95% CI 1.21-7.7.92, p=0.018) and hyperviscosity (HR 5.21 95% CI 4.21-27.8, p<0.0001) at cryoglobulinaemia diagnosis on multivariate analysis. Conclusions: This is the largest reported series describing the characteristics of IgM-associated type I cryoglobulinaemia. It is common amongst patients with monoclonal IgM disorders and approximately half of patients may be symptomatic. Distinct clonal populations are present in which type I cryoglobulinaemia may develop including an MYD88L265P WM clone and MYD88-wild type CAD/anti-MAG clone. Treatment may be required selectively in those with hyperviscosity, cutaneous or renal involvement, in a short time from diagnosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Monoclonal Gammopathy of Undetermined Significance (MGUS) with Multiple Paraproteins: Results from the Population-Based Istopmm Screening Study

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is the precursor of multiple myeloma (MM) and related disorders. It is characterized by asymptomatic presence of monoclonal immunoglobulins (paraproteins) on serum protein electrophoresis (SPEP) and immunofixation electrophoresis (IFE). Previous smaller studies have found that in approximately 3% of MGUS cases, more than one paraprotein is observed. The isotype patterns, clinical implications, and underlying biology of these multiple paraproteins (MP) are poorly understood. To our knowledge, we have performed the first large, prospective study of MGUS cases with multiple paraproteins. Methods: Data were acquired from the ongoing iStopMM study, a population-based screening study for MGUS and randomized trial of follow-up strategies. A total of 75,422 Icelanders over 40 years old were screened for MGUS by SPEP and IFE. Two-thirds of those with MGUS were randomized to further evaluation and follow-up. Participants with a paraprotein on SPEP and IFE were included in the study. Those with previous MM or related disease, paraprotein ≥3.0 g/dL, or an involved to uninvolved free light chain (FLC) ratio ≥100 were excluded. Those who had more than one monoclonal peak on IFE at baseline were defined as having MP. Baseline characteristics of those with MP and a single paraprotein were then compared. In participants who were followed at the study clinic, rates of progression to MM, smoldering MM (SMM), Waldenström macroglobulinemia (WM) and other related disorders were compared using logistic regression, adjusting for age. Available next generation flow cytometry (NGF) analyses of bone marrow in those with MP (MM-MRD panel) were reviewed. Results: A total of 3,358 individuals with at least one paraprotein were included in the study, of whom 314 (9.4%) had MP. Persons with MP were slightly older (72.1 vs 68.9 years p<0.001) and more likely to be male (59% vs 53% p=0.01). Of those with MP, 75% had two paraproteins. The most common paraproteins were IgG (47% of spikes) and IgM (36% of spikes). IgA and kappa or lambda spikes without a heavy chain were less common (11% and 6% of spikes) (Table). Having an IgM paraprotein was associated with a higher number of paraproteins (mean: 2.4 vs 2.2 p=0.03). After a median follow-up of 4.0 (range: 1.3-5.4) years, 59% of those with MP never had MP detected again and 42% of paraproteins were not observed again. Of the IgG, IgM, and IgA paraproteins detected at baseline, 36%, 40%, and 46% were not detected during follow-up and 81% of kappa or lambda bands were not observed again. The rate of later having a normal IFE was similar in those with and without MP (10% vs 7%; odds ratio (OR) 1.53, 95% confidence interval (CI) 0.88-2.52, p=0.11). There was no difference in the proportion diagnosed with SMM, SWM, or WM. None with MP at baseline progressed to MM, compared with 1% (n=18) of those with a single paraprotein (Table). NGF was available for 19 participants with MP, of whom 10 had SMM and 9 had MGUS. Two phenotypically distinct abnormal plasma cell populations were observed in 3 cases, a single phenotypically abnormal population was found in 13 (68%), and in 3 MGUS cases, no abnormal plasma cell population was detected. Discussion: In this large, population-based screening study with 75,422 participants, we found MP to be more common in MGUS (9.4%) than previously observed, and to be associated with older age and male sex. IgM paraproteins were more common in those with MP and were associated with a higher number of paraproteins. Over half of those with MP were later found to a have a single paraprotein, and 42% of paraproteins were not observed again during follow-up. During a median of 4 years of follow-up, none with MP developed MM. We speculate that MP could in some cases be caused by a strong or defective but transient immune response and could be associated with lower risk of MGUS progression. Interestingly, we observed multiple abnormal monoclonal plasma cell populations in some with MP, but whether they develop from the same insult or independently is not clear. With the advent of mass spectrometry-based diagnostics the rate of MP is expected to increase significantly. Understanding their clinical implications and biology will therefore become more important in guiding clinical practice. Mass spectrometry results for this cohort are pending and will shed more light on the prevalence, implications, and underlying biology of MP in MGUS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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

Persistence of Monoclonal Gammopathies in Serial Samples from a US Population-Based Screening Study

Background: The prevalence of monoclonal gammopathy of undetermined significance (MGUS) in a population at high risk of developing multiple myeloma (MM) was recently described in a US screening study. In a high-risk population, MGUS prevalence was measured as 6% by serum protein electrophoresis with immunofixation (SPEP/IFX) and 13% by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). Screening by MALDI-TOF MS allowed for the detection of monoclonal proteins (M-proteins) below the threshold of detection of gel-based assays, that was referred to as Monoclonal Gammopathy of Indeterminate Potential (MGIP). MGIP was found in 25% of the screened cohort and was significantly associated with aging. Other studies indicated that MGUS and MGIP detected by MS may be transient and their detection may not be critical for long term outcomes. Therefore, we aimed to determine the fate of M-proteins detected by MS in a US population-based study. Methods: High-risk individuals enrolled in the study include those who self-identify as Black or have a family history of hematologic malignancies or a precursor condition to MM. Samples that tested positive for MGUS (M-protein >= 0.2 g/L) by MALDI-TOF MS were confirmed using clinically approved assays and results were returned to participants. All participants who had an M-protein detected at baseline by MALDI-TOF MS were invited to submit follow-up samples to investigate the fate of the M-proteins detected at the MGIP and MGUS levels. Serum was analyzed using the Binding Site Group's EXENT® assay based on MALDI-TOF MS for the identification and quantification of M-proteins. Persistence of the M-protein detected at baseline was defined as the presence of the same isotype M-protein on a serial sample and within +/-5 mass to charge ratio on mass spectra. All serial samples where the M-protein was not detected by MALDI-TOF MS were reflex tested to liquid chromatography (LC) MS. Results: We analyzed 262 multi-timepoint samples collected from 102 participants who tested positive for an M-protein, with a median follow-up of 336 days (Range 36 - 1,240; IQR 141 - 737). The median age at screening was 60.8 years, 65 (64%) participants were female, 9 (9%) self-identified as Black, and 93 (91%) were non-Black and reported a family history of hematologic malignancy. At baseline, 66 (65%) participants had MGIP (M-protein <0.2g/L) and 36 (35%) had MGUS (M-protein >=0.2/L) measured by MALDI-TOF MS. All participants with MGIP were negative at baseline by SPEP/IFX, while among those with MGUS at baseline, 25/36 (69%) participants had an M-protein detected by SPEP/IFX. At baseline, the distribution of isotypes was 21% IgG, 17% IgA, and 62% IgM for MGIP and 69% IgG, 17% IgA, and 14% IgM for MGUS. For all 102 cases, their most recent serial samples were tested by MALDI-TOF MS or LC-MS. 60/66 (91%) of the MGIP cases were re-confirmed on serial sampling, with a median follow-up time of 504 days (Range 41 - 1,240; IQR 149 - 888). As for MGUS, 36/36 (100%) of cases detected at baseline persisted on serial sampling, with a median follow-up time of 239 days (Range 36 - 1105; IQR 103 - 628) (Figure 1). Time from baseline to serial sampling was not associated with persistence. In 12 participants so far, M-proteins detected by MS were seen to persist for more than 3 years after baseline testing. In 5 of the MGIP cases, M-protein concentration measured by MALDI-TOF MS increased from MGIP level to above the MGUS threshold. These participants had a median baseline M-protein concentration of 0.14 g/L (Range 0.13 - 0.17 g/L; IQR 0.13 - 0.14), which was in the upper MGIP concentration level, and had a median follow-up time of 532 days (Range 171 - 1,127; IQR 302 - 570). Of these, 3 persisted as IgG, 1 IgA, and 1 IgM isotypes. Conclusion: We present the first longitudinal analysis of M-proteins detected by MS, including those below the threshold of detection of gel-based assays, in a US population-based screening study. Results confirm the persistence of 91% of MGIP and 100% of MGUS cases detected by MS. Some cases showed increasing M-protein concentration, crossing the threshold of detection by gel-based assays. Additional studies are underway to further validate our findings in a larger cohort with longer follow-up time. Testing serial samples with increasing M-protein concentration by gel-based assays will help better understand the significance of early detection of MGIP cases by MS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Prognostic impact of MYD88 and CXCR4 mutations assessed by droplet digital polymerase chain reaction in IgM monoclonal gammopathy of undetermined significance and smouldering Waldenström macroglobulinaemia.

Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell-free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele-specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r=0.8; p < 0.001). CXCR4 C1013G was analysed in MYD88-mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r=0.9; p < 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88-mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular-based risk classification.

Prevalence of monoclonal gammopathy of undetermined significance in black South African men.

e20032 Background: Monoclonal gammopathy of undetermined significance (MGUS) is the precursor to multiple myeloma (MM). MM disproportionately affects black individuals, but the cumulative risk of progression from MGUS to malignancy does not differ by race. Hence, the racial disparities in MM incidence appear to arise from differences in the occurrence of MGUS. Nonetheless, MGUS has been studied mainly in white populations; the study that first described the natural history of MGUS was conducted by Kyle, et al. (2006) in 97.3% white Olmsted County, Minnesota. Methods: We determined the prevalence of MGUS among black South African men &gt;30 years of age at the Chris Hani Baragwanath Academic Hospital in Johannesburg. We conducted serum protein electrophoresis (SPEP) and free light chain (FLC) quantification and used the same criteria for MGUS as the Olmsted County studies: a monoclonal protein on SPEP or an abnormal FLC-ratio plus elevation in the appropriate FLC. We also investigated the association between MGUS and various clinical and behavioral factors. Results: The prevalence of MGUS in our cohort (n=386) was 8.03% (95%CI 5.32-10.74), nearly 1.6-fold higher than in Olmsted County males. In a univariable logistic regression model, MGUS was associated with HIV status (odds ratio (OR) 2.39, 95%CI 0.95-5.51), but in the adjusted model that also included body mass index (BMI) and cigarette use, the magnitude of the association decreased to an OR of 2.17 and was not statistically significant. MGUS was associated with current (vs. never) cigarette smoking in both univariable (OR 5.2, 95%CI 1.53-24.0) and multivariable (OR 4.11, 95%CI 1.08-20.4) models. Conclusions: Not only did we find the prevalence of MGUS in black South African men to be substantially higher than in white populations, but we also report that MGUS cases are associated with potentially modifiable risk factors. Building on this pilot study, a larger study is currently underway powered to confirm the relationship between MGUS and HIV, as well as between MGUS and cigarette smoking, in a black African population inclusive of both genders. Future studies designed to evaluate genetic and matched-environmental contributions may elucidate racial disparities and facilitate the development of strategies to prevent plasma cell malignancies.[Table: see text]

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

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

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

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