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

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

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

Forspárgildi IgA gigtarþáttar um árangur meðferðar með TNF-α hindrum við iktsýki: Hlutverk T stýrifruma

Inngangur: Iktsýki er sjálfsónæmissjúkdómur sem getur leitt til gríðarlegrar lífsgæðaskerðingar. Með tilkomu TNF-α hindra batnaði meðferð til mikilla muna. Enn eru þó sjúklingar sem ekki svara meðferð. Hækkaður IgA gigtarþáttur hefur verið tengdur við verri horfur í iktsýki. Myndun IgA mótefna og hugsanlega IgA gigtarþáttar er stýrt af T stýrifrumum. T stýrifrumur eru ónæmisbælandi undirhópur T fruma en skortur eða vanstarfsemi þeirra virðist hafa áhrif á meinmyndun iktsýki. Enn fremur virðist meðferð með TNF-α hindrum hafa áhrif á fjölda og virkni þessara fruma. Hugsanlega leiðir tenging IgA gigtarþáttar við T stýrifrumur til þess að IgA gigtarþáttur hafi forspárgildi um árangur þessarar meðferðar. Því er eitt markmið þessarar rannsóknar að kanna forspárgildi IgA gigtarþáttar um árangur meðferðar iktsýkissjúklinga með TNF-α hindrum. Annað markmið er að skoða betur samband T stýrifruma og IgA gigtarþáttar með því að þróa rannsóknarmódel á áhrifum T stýrifruma á sérhæfingu IgA myndandi plasmafruma og nýta það svo til að skoða muninn á þessum áhrifum eftir því hvort mælst hafði IgA gigtarþáttur í blóði eða ekki. Efni og aðferðir: Til að kanna forspárgildi IgA gigtarþáttar voru niðurstöður gigtarprófa á Landspítala tengd við upplýsingar um meðferðarárangur í ICEBIO. Til að kanna áhrif T stýrifruma á sérhæfingu plasmafruma voru fengin sýni úr iktsýkissjúklingum með og án IgA gigtarþáttar. T frumur úr sýnunum voru örvaðar til þroskunar í T stýrifrumur og settar í plasmafrumuhvetjandi aðstæður með B frumum. Fjöldi IgA myndandi plasmafruma var svo metinn í frumuflæðisjá. Niðurstöður: Ekki reyndist marktækur munur á meðferðarárangri eftir því hvort IgA gigtarþáttur mældist eða ekki (p=0,28 fyrir ACR og t=-0,83 fyrir DAS28CRP). Hægt var að sjá væga en ómarktæka tilhneigingu sjúklinga með mikið hækkaðan IgA gigtarþátt til að svara meðferð verr. (p um 0,12). Samkvæmt frumniðurstöðum virðast T stýrifrumur sjúklinga með IgA gigtarþátt bæla sérhæfingu IgA myndandi plasmafruma í minna mæli en T stýrifrumur sjúklinga án IgA gigtarþáttar. Umræður: Þó svo að ekki hafi fundist marktækur munur á meðferðarárangri eftir því hvort IgA gigtarþáttur mældist í blóði er þörf á stærra rannsóknarþýði til að útloka þann möguleika. Frumniðurstöður frumurannsókna benda til að vanstarfsemi T stýrifruma leiði til myndunar á IgA gigtarþætti. Enn þarf þó mikið að bæta rannsóknarmódelið áður en hægt er að draga ályktanir af því í sinni núverandi mynd

Peripheral Neuropathy in MGUS and Progression to Amyloid Light-Chain Amyloidosis: A Population-Based Study Including 15,351 MGUS Cases

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding

Validity of chronic disease diagnoses in Icelandic healthcare registries.

To access publisher's full text version of this article click on the hyperlink belowAims: To evaluate the validity of recorded chronic disease diagnoses in Icelandic healthcare registries. Methods: Eight different chronic diseases from multiple sub-specialties of medicine were validated with respect to accuracy, but not to timeliness. For each disease, 30 patients with a recorded diagnosis and 30 patients without the same diagnosis were randomly selected from >80,000 participants in the iStopMM trial, which includes 54% of the Icelandic population born before 1976. Each case was validated by chart review by physicians using predefined criteria. Results: The overall accuracy of the chronic disease diagnoses was 96% (95% CI 94-97%), ranging from 92 to 98% for individual diseases. After weighting for disease prevalence, the accuracy was estimated to be 98.5%. The overall positive predictive value (PPV) of chronic disease diagnosis was 93% (95% CI 89-96%) and the overall negative predictive value (NPV) was 99% (95% CI 96-100%). There were disease-specific differences in validity, most notably multiple sclerosis, where the PPV was 83%. Other disorders had PPVs between 93 and 97%. The NPV of most disorders was 100%, except for hypertension and heart failure, where it was 97 and 93%, respectively. Those who had the registered chronic disease had objective findings of disease in 96% of cases. Conclusions: When determining the presence of chronic disease, diagnosis data from the Icelandic healthcare registries has a high PPV, NPV and accuracy. Furthermore, most diagnoses can be confirmed by objective findings such as imaging or blood testing. These findings can inform the interpretation of studies using diagnostic data from the Icelandic healthcare registries. Keywords: Chronic diseases; Iceland; comorbidity; data accuracy; registries; validation study.Black Swan Research Initiative by the International Myeloma Foundation Icelandic Centre for Research European Research Council (ERC) University of Iceland Landspitali University Hospital Icelandic Cancer Societ