Development of a Multivariable Model to Predict the Need for Bone Marrow Sampling in Persons With Monoclonal Gammopathy of Undetermined Significance : A Cohort Study Nested in a Clinical Trial.

BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic precursor conditions to multiple myeloma and related disorders. Smoldering multiple myeloma is distinguished from MGUS by 10% or greater bone marrow plasma cells (BMPC) on sampling, has a higher risk for progression, and requires specialist management. OBJECTIVE: To develop a multivariable prediction model that predicts the probability that a person with presumed MGUS has 10% or greater BMPC (SMM or worse by bone marrow criteria) to inform the decision to obtain a bone marrow sample and compare its performance to the Mayo Clinic risk stratification model. DESIGN: iStopMM (Iceland Screens, Treats or Prevents Multiple Myeloma), a prospective population-based screening study of MGUS. (ClinicalTrials.gov: NCT03327597). SETTING: Icelandic population of adults aged 40 years or older. PATIENTS: 1043 persons with IgG, IgA, light-chain, and biclonal MGUS detected by screening and an interpretable bone marrow sample. MEASUREMENTS: Monoclonal gammopathy of undetermined significance isotype; monoclonal protein concentration; free light-chain ratio; and total IgG, IgM, and IgA concentrations were used as predictors. Bone marrow plasma cells were categorized as 0% to 4%, 5% to 9%, 10% to 14%, or 15% or greater. RESULTS: The c-statistic for SMM or worse was 0.85 (95% CI, 0.82 to 0.88), and calibration was excellent (intercept, -0.07; slope, 0.95). At a threshold of 10% predicted risk for SMM or worse, sensitivity was 86%, specificity was 67%, positive predictive value was 32%, and negative predictive value was 96%. Compared with the Mayo Clinic model, the net benefit for the decision to refer for sampling was between 0.13 and 0.30 higher over a range of plausible low-risk thresholds. LIMITATION: The prediction model will require external validation. CONCLUSION: This accurate prediction model for SMM or worse was developed in a population-based cohort of persons with presumed MGUS and may be used to defer bone marrow sampling and referral to hematology. PRIMARY FUNDING SOURCE: International Myeloma Foundation and the European Research Council.

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

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

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

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

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

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

Bone disease in monoclonal gammopathy of undetermined significance: results from a screened population-based study.

Previous studies have shown that individuals with monoclonal gammopathy of undetermined significance (MGUS) have an increased risk of fractures, although the underlying mechanisms remain unknown. Our aim was to analyze bone mineral density (BMD), bone volume, and risk of fractures among individuals with MGUS. We performed a screening using the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study cohort, consisting of 5764 elderly individuals, identifying 300 individuals with MGUS, and 275 with light-chain MGUS. Quantitative computerized tomography was performed in the lumbar spine and hip to evaluate BMD and bone geometry. Analysis of variance and the Tukey honest significance test were used to compare the groups. Hospital records were used to record fractures, with a mean follow-up of 6.9 years. Cox proportional hazard was used to compare fracture risk. No difference was found in BMD between subjects with MGUS and others in the spine (P = .34) or in total hip (P = .30). Individuals with MGUS had a significant increase in bone volume compared with others in the spine (P < .001) and total hip (P < .001). Overall, the risk of fractures was not significantly increased in individuals with MGUS (hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.94-1.50). Men with MGUS had a significantly increased fracture risk, compared with other men (HR, 1.46; 95% CI, 1.03-2.08). Our results show that although individuals with MGUS do not have decreased BMD, bone volume is increased, and MGUS men have a 50% increased fracture risk. These results indicate that bone disease and fractures in MGUS differ from processes known from osteoporosis.

[Chronic lymphocytic leukemia in Iceland from 2003 to 2013: Incidence, presentation and diagnosis].

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is characterized by the proliferation of monoclonal B-lymphocytes. MBL (monoclonal B-cell lymphocytosis) is considered a precursor state of the disease. Although CLL is incurable it is an indolent disorder and often detected incidentally on routine blood counts. Until now little information has been available on CLL in Iceland, including the incidence, diagnosis, symptoms or MBL precursor state. MATERIAL AND METHODS: This is a retrospective, descriptive study including CLL patients diagnosed in Iceland over the years 2003-2013. Registries of patients with a CLL diagnosis were obtained from the Icelandic Cancer Registry, Landspitali National University Hospital and the Medical Center in Mjódd. Medical records were reviewed for information on symptoms, diagnosis and treatment. Survival data and causes of death were obtained from national registries. RESULTS: The number of patients diagnosed with CLL over the study period was 161 (109 males, 52 females). The calculated incidence was 4.55/100,000, and the age-standardized incidence was 3.00/100,000. Mean age at diagnosis was 70.9 years (range 35-96 years). The Icelandic Cancer Registry lacked information on 28 patients (17.4%). The initial diagnosis of CLL was obtained exclusively with flow cytometry in 47.2% of cases. Symptoms were present at diagnosis in 67 of 151 patients (44.4%). One third of the group received chemotherapy and the average time to treatment was 1.3 years. Five-year survival was 70% and median survival was 9.4 years. Elevated lymphocyte counts (≥4,0x109/L) in peripheral blood prior (0.1 to 13.4 years) to diagnosis of CLL was identified in 85 of 99 CLL patients (85.9%). CONCLUSION: The incidence of CLL in Iceland is similar to other Western countries. The registration of CLL cases in the Icelandic Cancer Registry must be improved, especially in cases where diagnosis is based solely on flow cytometry. Elevated lymphocyte counts were present in a large proportion of cases prior to the diagnosis of CLL. KEY WORDS: Chronic lymphocytic leukemia, CLL, monoclonal B-cell lymphocytosis, MBL, incidence, diagnosis. Correspondence: Anna Margret Halldorsdottir, annamha@landspitali.is.

Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.

Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10(-9) and P=6.4 × 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).

Inherited polymorphisms in hyaluronan synthase 1 predict risk of systemic B-cell malignancies but not of breast cancer.

Genetic variations in the hyaluronan synthase 1 gene (HAS1) influence HAS1 aberrant splicing. HAS1 is aberrantly spliced in malignant cells from multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM), but not in their counterparts from healthy donors. The presence of aberrant HAS1 splice variants predicts for poor survival in multiple myeloma (MM). We evaluated the influence of inherited HAS1 single nucleotide polymorphisms (SNP) on the risk of having a systemic B cell malignancy in 1414 individuals compromising 832 patients and 582 healthy controls, including familial analysis of an Icelandic kindred. We sequenced HAS1 gene segments from 181 patients with MM, 98 with monoclonal gammopathy of undetermined significance (MGUS), 72 with Waldenstrom macroglobulinemia (WM), 169 with chronic lymphocytic leukemia (CLL), as well as 34 members of a monoclonal gammopathy-prone Icelandic family, 212 age-matched healthy donors and a case-control cohort of 295 breast cancer patients with 353 healthy controls. Three linked single nucleotide polymorphisms (SNP) in HAS1 intron3 are significantly associated with B-cell malignancies (range p = 0.007 to p = 10(-5)), but not MGUS or breast cancer, and predict risk in a 34 member Icelandic family (p = 0.005, Odds Ratio = 5.8 (OR)), a relatively homogeneous cohort. In contrast, exon3 SNPs were not significantly different among the study groups. Pooled analyses showed a strong association between the linked HAS1 intron3 SNPs and B-cell malignancies (OR = 1.78), but not for sporadic MGUS or for breast cancer (OR<1.0). The minor allele genotypes of HAS1 SNPs are significantly more frequent in MM, WM, CLL and in affected members of a monoclonal gammopathy-prone family than they are in breast cancer, sporadic MGUS or healthy donors. These inherited changes may increase the risk for systemic B-cell malignancies but not for solid tumors.

Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial.

The Nordic Myeloma Study Group conducted an open randomized trial to compare bortezomib as consolidation therapy given after high-dose therapy and autologous stem cell transplantation (ASCT) with no consolidation in bortezomib-naive patients with newly diagnosed multiple myeloma. Overall, 370 patients were centrally randomly assigned 3 months after ASCT to receive 20 doses of bortezomib given during 21 weeks or no consolidation. The hypothesis was that consolidation therapy would prolong progression-free survival (PFS). The PFS after randomization was 27 months for the bortezomib group compared with 20 months for the control group (P = .05). Fifty-one of 90 patients in the treatment group compared with 32 of 90 controls improved their response after randomization (P = .007). No difference in overall survival was seen. Fatigue was reported more commonly by the bortezomib-treated patients in self-reported quality-of-life (QOL) questionnaires, whereas no other major differences in QOL were recorded between the groups. Consolidation therapy seemed to be beneficial for patients not achieving at least a very good partial response (VGPR) but not for patients in the ≥ VGPR category at randomization. Consolidation with bortezomib after ASCT in bortezomib-naive patients improves PFS without interfering with QOL. This trial was registered at www.clinicaltrials.gov as #NCT00417911.

Familial predisposition to monoclonal gammopathies: deviations in B-cell biology.

Monoclonal gammopathies are associated with advancing age but a familial predisposition has been recognized for several decades. A functional phenotype, characterized by increased immunoglobulin (Ig) production after mitogen stimulation has been identified in healthy members of 4 families showing a predisposition toward IgM and IgG/IgA disorders. B cells from these hyperresponders do not show increased rates of Ig gene translocations and no aberrations were detected in an in vitro model of the germinal center reaction. Array-based comparative genome hybridization revealed deletions of Ig genes in peripheral blood B cells, as expected. In addition, random changes were detected throughout the genome, presumably reflecting off-target activation-induced cytidine deaminase (AID) activity. These random changes were significantly less prevalent in B cells from hyperresponders, indicating less exposure to the germinal center environment during maturation.

Familial paraproteinemia: hyper-responsive B-cells as endophenotype.

The prevalence of paraproteinemias or monoclonal gammopathies increases with age. No other major risk factors have been recognized, but significant associations have been reported with chronic antigen exposure, agricultural environment, and family history. In around 130 families reported worldwide, IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) occurs with multiple myeloma (MM) whereas Waldenström's macroglobulinemia (WM) is linked to IgM MGUS. Of the 8 multi-case families described here, 5 are remarkable for including both IgG/IgA and IgM type disorders. In the remaining 3 families IgG/IgA MGUS and MM occurred with Hodgkin disease and T-cell malignancies. These different patterns of familial paraproteinemia indicate different genetic backgrounds. A previously described functional phenotype of hyper-responsive B lymphocytes fulfils criteria for being an endophenotype and may be related to raised serum IgM. Identifying an endophenotype is important to ensure correct classification of affected family members and thus enhance the power of genetic studies.

Familial monoclonal gammopathy: hyper-responsive B cells in unaffected family members.

BACKGROUND: In Iceland, eight families have been identified with multiple cases of monoclonal gammopathies (MG) and other lymphoproliferative diseases. In one of these families with several cases of monoclonal gammopathy of undetermined significance (MGUS) and Waldenströms macroglobulinemia, in vitro stimulation with poke-weed mitogen revealed hyper-responsive B cells showing increased immunoglobulin production in one-third of disease-free family members. DESIGN AND METHODS: In this study, the families were further traced and the list of names produced was compared with The Icelandic Cancer Registry (ICR) to find all recent cases of lymphoproliferative diseases. First-degree relatives and descendants older than 20yrs of age (n=350) were selected for screening for paraprotein. Selected family members were tested for B-cell hyper-responsiveness and the lymphocyte phenotype was analysed by flow cytometry. RESULTS: Comparison of the total list of 4370 family members with the ICR revealed 22 new cases and screening for serum paraprotein identified nine new cases of MG, eight being first-degree relatives of known probands. Sixty cases of lymphoproliferative diseases are currently known within the eight families, five of them containing both IgG/A and IgM disorders. Twelve hyper-responders (HR) were identified in four families, eight from one family, of whom four were known already. Stimulated B cells from HR had a significantly higher proportion of CD27(+) memory/plasma cells than controls. CONCLUSION: Identification of new affected family members by screening confirms a hereditary predisposition to B-cell proliferative diseases. Contrary to most studies, IgG/A and IgM disorders occurred together in five families. In four families, enhanced B-cell responsiveness was found in healthy subjects clustered around cases.

Familial predisposition to monoclonal gammopathy of unknown significance, Waldenström's macroglobulinemia, and multiple myeloma.

The medical literature contains reports of around 130 families with two or more cases of MM, MGUS, or WM. An Icelandic family with multiple cases of MGUS, WM, and lymphoma was first described in 1978. In vitro testing of peripheral blood lymphocytes revealed increased production of immunoglobulins in response to poke-weed mitogen in 10 out of 35 family members, referred to as hyperresponders (HR). Enhanced B-cell survival after stimulation was associated with prolonged expression of Bcl-2. A population-based cancer registry study of 218 MM patients identified 7 additional families. Nine new cases of monoclonal gammopathy were detected by the screening of 350 family members. Further testing confirmed previously identified HR in the originally described family as well as detecting new cases. Only two HR were found in the recently identified families. The long-term aim is to identify the genetic background(s) and biology predisposing to the emergence of a persistent clone of immunoglobulin-producing cells.

Monoclonal gammopathy: natural history studied with a retrospective approach.

The aim of this study was to examine the natural history of monoclonal gammopathy using a retrospective approach and a long observation period. Protein electrophoresis (PE) and immunofixation (IF) was performed on frozen prediagnosis serum samples from 65 multiple myeloma (MM) and 10 Waldenström's macroglobulinemia (WM) cases. Paraprotein was found in 28% and 46% of the samples from cases using PE and IF respectively. The type of paraprotein was IgA in 33.4% of cases, IgG in 57%, and IgM in 8.5%. Excluding light chain or non-secretory disease, 72 % of MM cases had a prodromal MGUS phase within 10 years of diagnosis MM and WM were preceded by MGUS in at least half of the cases, confirming the premalignant nature of this condition.

Disseminated invasive aspergillosis in a patient with acute leukaemia.

A 46-year-old previously healthy woman was diagnosed with acute lymphoblastic leukaemia. The induction phase was complicated by alpha-haemolytic streptococcal bacteremia which responded to antibacterial therapy. Subsequently, the patient developed pneumonie due to Chlamydiapneumoniae which responded to macrolides. Following this infection the patient developed recurrent fever and new pulmonary infiltrates were noted. Bronchoscopy was performed and treatment was administered with liposomal amphotericin B (L-AmB, AmBisome) for two days, but was complicated by acute renal failure. Aspergillus fumigatus was cultured from bronchoalveolar lavage fluid [corrected] L-AmB was discontinued and voriconazole and caspofungin were administered. Despite aggressive antifungal therapy the patient developed progressive invasive infection, with central nervous system involvement as well as lesions appearing in the kidneys and liver. The patient died one week following the diagnosis of aspergillosis.