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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., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2540.

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., (© 2023. The Author(s).)

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.

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., (© 2023. The Author(s).)

Various epidemiological studies, including case reports and -series in addition to larger, population-based studies, have reported an increased prevalence of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma in individuals with a prior history of immune-related conditions. This is believed to support the role of chronic antigen stimulation in the pathogenesis of these conditions. In this short review, we summarize some of the largest population-based studies researching autoimmune diseases, infections, and the subsequent risk of MGUS, and discuss our understanding on its etiology and pathogenesis. Furthermore, we highlight important methodological limitations of previous studies in the field, but almost all studies on MGUS have been based on clinical, possibly biased, cohorts. Finally, we discuss future directions in researching the associations of MGUS and other disorders, including immune-related conditions, where screening studies play an important role., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sigurbergsdóttir, Love and Kristinsson.)

Patients with multiple myeloma (MM) have an increased risk of venous thrombosis. Interestingly, excess risk of venous thromboembolism has been observed among patients with monoclonal gammopathy of undetermined significance (MGUS). Using population-based data from Sweden, we assessed the risks of venous and arterial thrombosis in 18,627 MM and 5326 MGUS patients diagnosed from 1958 to 2006, compared with 70,991 and 20,161 matched controls, respectively. At 1, 5, and 10 years after MM diagnosis, there was an increased risk of venous thrombosis: hazard ratios (95% confidence intervals) were 7.5 (6.4-8.9), 4.6 (4.1-5.1), and 4.1 (3.8-4.5), respectively. The corresponding results for arterial thrombosis were 1.9 (1.8-2.1), 1.5 (1.4-1.6), and 1.5 (1.4-1.5). At 1, 5, and 10 years after MGUS diagnosis, hazard ratios were 3.4 (2.5-4.6), 2.1 (1.7-2.5), and 2.1 (1.8-2.4) for venous thrombosis. The corresponding risks for arterial thrombosis were 1.7 (1.5-1.9), 1.3 (1.2-1.4), and 1.3 (1.3-1.4). IgG/IgA (but not IgM) MGUS patients had increased risks for venous and arterial thrombosis. Risks for thrombosis did not vary by M-protein concentration (> 10.0 g/L or < 10.0 g/L) at diagnosis. MGUS patients with (vs without) thrombosis had no excess risk of MM or Waldenström macroglobulinemia. Our findings are of relevance for future studies and for improvement of thrombosis prophylaxis strategies.

Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.

Waldenström's macroglobulinemia (WM) is associated with a precursor condition, monoclonal gammopathy of undetermined significance (MGUS) of immunoglobulin-M (IgM) type. The etiology of these conditions is unknown. Recent studies at the population level have provided new data regarding familial aggregation of these disorders and other B-cell malignancies. Studies of familial clusters of WM have demonstrated an increased frequency of IgM MGUS compared with the general population and have provided new data suggesting that the phenotypic spectrum might also include polyclonal gammopathy and hypoglobulinemia. While the preponderance of immunoglobulin abnormalities in relatives of WM cases involves IgM, other immunoglobulin types (IgG and IgA) might also be affected. Large collaborative studies are needed to confirm these findings, which present an opportunity to define the earliest lesion(s) in the WM oncogenic pathway.

Patients with multiple myeloma (MM) have an increased risk of deep venous thrombosis (DVT), particularly when treated with immunomodulatory drugs. Recently, 2 small hospital-based studies observed persons with the MM precursor condition, monoclonal gammopathy of undetermined significance (MGUS), to be at increased risk of developing DVT. Among 4 196 197 veterans hospitalized at least once at US Veterans Affairs hospitals, we identified a total of 2374 cases of MGUS, and 39 272 persons were diagnosed with DVT (crude incidence 0.9 per 1000 person-years). A total of 31 and 151 DVTs occurred among MGUS and MM patients, respectively (crude incidence 3.1 and 8.7 per 1000 person-years, respectively; P < .01). Compared with the entire study population, the relative risk (RR) of DVT after a diagnosis of MGUS and MM was 3.3 (95% confidence interval [CI], 2.3-4.7) and 9.2 (95% CI, 7.9-10.8), respectively. The most prominent excess risk of DVT was found during the first year after diagnosis of MGUS (RR = 8.4; 95% CI, 5.7-12.2) and MM (RR = 11.6; 95% CI, 9.2-14.5). Among 229 MGUS cases (9.5%) that progressed to MM, only one person had a DVT diagnosis before transformation. Our findings suggest the operation of shared underlying mechanisms causing coagulation abnormalities among patients with MGUS and MM.