Peripheral neuropathy and monoclonal gammopathy of undetermined significance : A population-based study including 15,351 cases and 58,619 matched controls

Funding Information: this research was supported by grants from the University of Iceland Research Fund, Icelandic Centre for Research (RANNIS), Landspitali University Hospital Research Fund, and Karolinska Institutet Foundations. Funding support for this publication was provided by the Memorial Sloan Kettering Core Grant (P30 CA008748) and the Perelman Family Foundation in collaboration with the Multiple Myeloma Research Foundation (MMRF) for OL. SR is a PhD candidate at the University of Iceland and this work is submitted in partial fulfilment of the requirement for a PhD. Funding Information: 1Faculty of Medicine, University of Iceland, Reykjavík, Iceland; 2Skåne University Hospital, Malmö/Lund, Sweden; 3Department of Medicine, Karolinska University Hospital Solna and Institutet, Stockholm, Sweden and 4Myeloma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Correspondence: SAEMUNDUR ROGNVALDSSON - [email protected] doi:10.3324/haematol.2019.239632 Funding: this research was supported by grants from the University of Iceland Research Fund, Icelandic Centre for Research (RANNIS), Landspitali University Hospital Research Fund, and Karolinska Institutet Foundations. Funding support for this publication was provided by the Memorial Sloan Kettering Core Grant (P30 CA008748) and the Perelman Family Foundation in collaboration with the Multiple Myeloma Research Foundation (MMRF) for OL. SR is a PhD candidate at the University of Iceland and this work is submitted in partial fulfilment of the requirement for a PhD.Peer reviewe

Diabetes mellitus and risk of plasma cell and lymphoproliferative disorders in 94,579 cases and 368,348 matched controls

this research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 (UAS) and supported by grants from Swedish Cancer Society (MB), Parker Institute of Cancer Immunotherapy Career Development Award (YD, UAS), International Myeloma Society Career Development Award, Paula and Rodger Riney Foundation, American Society of Hematology Clinical Research Training Institute Award and TREC Training Workshop R25CA203650 (PI: Melinda Irwin) (UAS). Copyright & Usage Copyright (c) 2022 Ferrata Storti Foundation Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Peer reviewe

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

Publisher Copyright: © 2023, The Author(s).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.Peer reviewe

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.Peer reviewe

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

Publisher Copyright: © 2022. The Author(s). © 2022. The Author(s).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.Peer reviewe

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

Publisher Copyright: © 2023, The Author(s).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.Peer reviewe

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

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.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadMonoclonal 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.Black Swan Research Initiative by the International Myeloma Foundation Icelandic Centre for Research European Research Council (ERC) University of Iceland Landspitali University Hospita

Klínísk þýðing góðkynja einstofna mótefnahækkunar: Aðferðafræðilegar lausnir til að rannsaka einkennalaust forstig

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic disorder caused by the accumulation of monoclonal immunoglobulin secreting cells in the bone marrow. The main clinical implication of MGUS is that it’s the precursor of multiple myeloma (MM) and related disorders. Current guidelines recommend indefinite follow-up of individuals with MGUS in order to detect MGUS progression. The benefits of this follow-up and of detecting MGUS have not been sufficiently studied but recent evidence has suggested that the detection of MGUS provides opportunities of early treatment in MM and related disorder at an asymptomatic stage and that such early treatment can significantly improve outcomes. Systematic screening may provide a means to vastly expand the availability of early treatment but has not been sufficiently studied. MGUS may also have other clinical significance with multiple studies associating the asymptomatic disorder with a wide range of non-malignant disorders. However, previous studies have been heavily afflicted by bias and the extent of these associations and their clinical relevance is not clear. The aim of this thesis is to further clarify the clinical significance of MGUS with an emphasis on the association of MGUS and non-malignant disease and to demonstrate methodologies that can significantly improve our understanding of this asymptomatic precursor disorder and its clinical significance. Four papers are presented. The first two papers apply alternative study designs and statistical methods to registry-based data on MGUS from Sweden to study the relationship between MGUS and peripheral neuropathy (PN) and fractures. The latter two papers pertain to the Iceland screens, treats, or prevents multiple myeloma study (iStopMM), a population-based screening study with the aim of gathering a population- based cohort of individuals screened for MGUS and to assess the benefits and harms of such screening in a clinical trial. The study is described in detail in paper three and the fourth paper demonstrates the opportunities to found in studying MGUS disease associations within the screened cohort of iStopMM by assessing the relationship of MGUS and coronavirus disease 2019 (COVID-19). In paper I and II, MGUS was found to be associated with PN and fractures. Based on the findings we hypothesized that PN is one of, at least, three causes of fractures in MGUS alongside undetected MM bone disease and MGUS inherent bone disease. In paper III, the recruitment of iStopMM is described with around 54% of eligible Icelanders (n=80,759) signing up to participate in the study. In paper IV, MGUS was unexpectedly not found to be associated with increased incidence or severity of COVID-19. v In conclusion, MGUS has clinical significance by being the precursor of MM and related disorders and by leading to non-malignant complications. The findings of this thesis confirm that previous studies have been afflicted by significant bias. Further studies, particularly within screened cohorts like that of iStopMM, are needed to further clarify the clinical significance of MGUS and to focus and improve care of individuals with MGUS.Á Góðkynja einstofna mótefnahækkun (e. monoclonal gammopathy of undetermined significance, MGUS) er einkennalaust ástand orsakað af uppsöfnun einstofna mótefnaframleiðandi frumna í beinmerg. Klínískt mikilvægi MGUS felst fyrst og fremst í því að það er forstig mergæxlis og skyldra sjúkdóma. Núgildandi leiðbeininagar ráðleggja eftirfylgd með einstaklingum með MGUS til að greina þróun þess yfir í illkynja sjúkdóma. Gagnsemi þessarar eftirfylgdar og þess að greina MGUS hefur þó ekki verið að fullu sönnuð en talsverðar vísbendingar eru um að með því að greina þróun MGUS yfir í illkynja sjúkdóma snemma megi grípa fyrr inn í og þannig bæta horfur í þeim sjúkdómum talsvert. Kerfisbundin skimun fyrir MGUS gæti verið leið til að auka aðgengi að slíkri snemmbúinni meðferð en ekki liggja fyrir neinar rannsóknir á slíkri skimun. Til viðbótar við að vera forstig illkynja sjúkdóma hefur MGUS verið tengt fjölda annarra sjúkdóma. Fyrri rannsóknir eru þó líklega nokkuð bjagaðar og enn er því óljóst hvaða sjúkdóma MGUS tengist raunverulega og hvaða klínísku þýðingu þær sjúkdómstengingar hafa. Markmið þessarar ritgerðar er að skýra klínískt mikilvægi MGUS, einkum með tilliti til sjúkdóma sem ekki eru illkynja. Ætlunin er að nota nýja aðferðarfræðilega nálgun sem getur stórbætt skilning okkar á MGUS og sjúkdómum sem því tengjast. Rigerðin byggir á fjórum greinum. Í grein I og II eru tengsl MGUS við úttaugamein og beinbrot skoðuð í sænskum gagnagrunni og öðruvísi aðferðarfræðilegri nálgun beitt á það gagnasett en áður hefur verið gert. Seinni tvær greinarnar byggja á rannsókninni Blóðskimun til bjargar. Rannsóknin er lýðgrunduð skimunarrannsókn fyrir MGUS og slembiröðuð rannsókn á eftirfylgd með það að markmiði að kanna gagnsemi og skaðsemi þess að skima fyrir MGUS. Rannsókninni og hönnun hennar er ítarlega lýst í grein III. Í grein IV eru gögn rannsóknarinnar notuð til að rannsaka tengsl MGUS og COVID-19 í því óbjagaða þýði einstaklinga með MGUS sem greinast með skimun í Blóðskimun til bjargar. Í grein I og II sýna niðurstöðurnar að MGUS tengist úttaugameini og beinbrotum. Auk þess benda niðurstöðurnar til þess að úttaugamein sé ein af a.m.k. þremur orsökum beinbrota í MGUS samhliða ógreindum mergæxlis beinasjúkdómi og MGUS beinasjúkdómi. Í grein III er öflun þátttakenda í Blóðskimun til bjargar lýst en alls skráðu 80,759 Íslendingar sig í rannsóknina. Í grein IV sáust nokkuð óvænt engin tengsl milli MGUS og tíðni eða alvarleika COVID-19. Niðurstöðurnar benda til að MGUS hafi klínískt mikilvægi. Það er bæði forstig illkynja sjúkdóma og tengist líklega öðrum sjúkdómum líka. Einnig staðfesta niðurstöðurnar fyrri grun um að eldri rannsóknir hafi byggt á bjöguðum þýðum sem hafa gefið okkur skakka mynd af umfangi tengsla MGUS við sjúkdóma og sýna glögglega mikilvægi þessi að rannsaka þessi tengsl innan skimaðra þýða eins og í Blóðskimun til bjargar. Slíkar rannsóknir eru nauðsynlegar til að skýra raunverulegt klínískt mikilvægi MGUS og með því betrumbæta eftirfylgd einstaklinga með MGUS og þannig vonandi horfur þeirra