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Importance: In recent years, there has been a focus on reducing the socioeconomic gap in survival for hematological malignant neoplasms. Understanding recent developments is important to develop further intervention to improve care., Objective: To investigate the temporal trend in associations of socioeconomic status (SES) with survival among 3 aggressive hematological malignant neoplasms: multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL)., Design, Setting, and Participants: This nationwide, population-based cohort study used retrospectively collected data from 3 clinical registries of patients diagnosed in Denmark between January 1, 2005, and December 31, 2020, with follow-up until December 31, 2021. Analyses were stratified by diagnosis year (2005-2009, 2010-2014, and 2015-2020). Participants were patients aged 25 to 65 years with hematological malignant neoplasms. Patients with missing data on education were excluded. Data were analyzed from October 14, 2022, to January 2, 2024., Exposure: Education was used as a proxy for SES and defined low- and high-SES groups based on the completion of tertiary education., Main Outcomes and Measures: The main outcome was overall survival (OS), analyzed using Kaplan-Meier (log rank) method and Cox proportional hazards regression adjusted for age, sex, performance status, comorbidities, and disease-specific prognostic indices. Two-year OS through time and survival difference were estimated using flexible parametric survival models., Results: A total of 5677 patients (median [IQR] age, 58 [51-62] years; 3177 [57.0%] male) were assessed, including 1826 patients with MM, 1236 patients with AML, and 2509 patients with DLBCL. The 2-year OS increased over time for patients with MM (78.8% [95% CI, 75.4%-82.3%] to 91.4% [95% CI, 89.3%-93.5%]), AML (42.2% [95% CI, 37.8%-47.1%] to 52.7% [95% CI, 48.0%-57.9%]), and DLBCL (80.1% [95% CI, 77.4%-82.8%] to 88.1% [95% CI, 86.0%-90.3%]). For MM and DLBCL, no association of SES with survival was observed after adjustment (MM: hazard ratio [HR], 0.99 [95% CI, 0.85-1.15]; DLBCL: HR, 1.08 [95% CI, 0.91-1.29]). For AML, a negative association was observed between low SES and survival (HR, 1.49 [95% CI, 1.25-1.76]), but the association was attenuated in recent years. The difference in hazard for patients with low SES and AML was observed in the first 2 years after diagnosis., Conclusions and Relevance: These findings suggest that survival has improved among patients with these hematological malignant neoplasms. While patients with MM and DLBCL had increased survival in all groups, disparities were observed in AML outcomes, primarily in the first years after diagnosis. These results suggest that differences originate in factors specific to AML.

Background: Decisions regarding maintenance therapy in patients with multiple myeloma should be based on both treatment efficacy and health-related quality of life (HRQL) consequences. In the CARFI trial, patients with first relapse of multiple myeloma underwent salvage autologous stem cell transplantation (salvage ASCT) before randomization to carfilzomib-dexamethasone maintenance therapy (Kd) or observation. The primary clinical endpoint was time to progression, which was extended by 8 months by Kd. The aim of this paper is to present the all HRQL endpoints of the CARFI trial including the HRQL effect of Kd maintenance therapy relative to observation. The primary HRQL endpoint was assessed by EORTC QLQ-C30 Summary score (QLQ-C30-sum) at 8 months follow-up. A key secondary HRQL endpoint was quality-adjusted progression-free-survival (QAPFS)., Methods: HRQL was assessed with EORTC QLQ-C30, EORTC QLQ-MY20 and FACT/GOG-Ntx at randomization and every second month during follow-up. HRQL data were analyzed with linear mixed effect models until 8 months follow-up. QAPFS per individual was calculated by multiplying progression-free survival (PFS) by two quality-adjustment metrics, the QLQ-C30-sum and EORTC Quality of Life Utility Measure-Core 10 dimensions (QLU-C10D). The QAPFS per treatment group was estimated with the Kaplan-Meier method. P < 0.05 was used for statistical significance, and a between-group minimal important difference of 10 points was interpreted as clinically relevant for the QLQ-C30-sum., Results: 168 patients were randomized. HRQL questionnaire compliance was 93%. For the QLQ-C30-sum, the difference of 4.62 points (95% confidence interval (CI) -8.9: -0.4, p = 0.032) was not clinically relevant. PFS was 19.3 months for the Kd maintenance group and 16.8 months for the observation group; difference = 2.5 months (95% CI 0.5; 4.5). QAPFS based on the QLQ-C30-sum for the Kd maintenance group was 18.0 months (95% CI 16.4; 19.6) and for the observation group 15.0 months (95% CI 13.5; 16.5); difference = 3.0 months (95% CI 0.8-5.3). QAPFS based on the QLU-C10D for the Kd maintenance group was 17.5 months (95% CI 15.9; 19.2) and 14.0 months (95% CI 12.4; 15.5) for the observation group; difference = 3.5 months (95% CI 1.1-5.9)., Conclusions: Kd maintenance therapy after salvage ASCT did not adversely affect overall HRQL, but adjustment for HRQL reduced the PFS compared to unadjusted PFS. PFS of maintenance therapy should be quality-adjusted to balance the benefits and HRQL impact., (© 2024. The Author(s).)

Background: The aetiology of multiple myeloma (MM) is unknown but various environmental exposures are suspected as risk factors. We present the first paper analysing the geographical distribution of MM in Denmark at the municipal level to investigate variations that could be explained by environmental exposures., Methods: Patients diagnosed with MM in Denmark during 2005-2020 were identified from nationwide registries and grouped into the 98 Danish municipalities based on residence. The age- and sex-standardised incidence rate (SIR) of each municipality was compared to the national incidence in a funnel plot with 95% control limits. Differences in SIRs of rural, suburban, and urban areas were evaluated with incidence rate ratios., Results: In total, 5243 MM patients were included. Overall, we found a heterogeneous geographical distribution of MM and a potential hotspot in southern Denmark. This hotspot contains three municipalities with SIRs above the 95% control limit assuming considerably higher rate of MM compared to the national incidence rate. A significant higher SIR was found in rural areas compared to urban areas., Conclusion: The geographical distribution of MM in Denmark indicates that the risk of developing MM depends on place of residence probably due to environmental factors., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments., Methods: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression., Results: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 × 10-5., Conclusions: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression., Trial Registration: NCT01208766., (© 2022. The Author(s).)

Objective: We describe real-world evidence (RWE) from the nationwide Swedish and Danish registries that provide important information on incidence and outcome in multiple myeloma (MM)., Method: First line treatment data on more than 10.000 MM patients from Denmark and Sweden between 2005-2018 are presented. Key results from research conducted within the Swedish and Danish myeloma registries are summarized, describing subgroups of patients with comorbidity, myeloma complications, and early relapse., Results: We show that national guidelines, generated on results from randomized clinical trials (RCTs) are rapidly implemented and improve overall survival (OS). We find that both the incidence of MM and the median age at diagnosis is higher in national registries compared to results from referral centres, indicating a more complete coverage. This highlights the need of validation of prognostic scoring systems and indices in e.g., SMM and high-risk MM in a real- world-population. We show that these subgroups are unlikely to be captured in RCTs with narrow inclusion and exclusion criteria, that they have worse survival, and are in need of new treatment approaches., Conclusion: National registries that include all MM patients are an important source of knowledge on epidemiology, treatment and outcome with implications for the planning of MM care. Despite the introduction of new and better treatments, rapidly implemented in our countries, our registries uncover subgroups of patients that still have inferior outcome. Our RWE can help to identify important research questions to be studied in further clinical trials also in patients currently not included in RCTs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: We investigated the efficacy and safety of carfilzomib-containing induction before salvage high-dose melphalan with autologous stem-cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma., Methods: This randomised, open-label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re-induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 → 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86)., Results: Median time to progression (TTP) after randomisation was 25.1 months (22.5-NR) in the carfilzomib-dexamethasone maintenance group and 16.7 months (14.4-21.8) in the control group (HR 0.46, 95% CI 0.30-0.71; P = .0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections., Conclusion: In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well-tolerated with manageable toxicity., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Purpose: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial., Patients and Methods: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS)., Results: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable., Conclusion: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone., Competing Interests: Pieter SonneveldConsulting or Advisory Role: Celgene, Janssen, Amgen, Karyopharm Therapeutics, CARsgen TherapeuticsResearch Funding: Janssen, Amgen, Skyline Diagnostics Meletios A. DimopoulosHonoraria: Amgen, Takeda, Janssen-Cilag, Bristol Myers Squibb, BeigeneConsulting or Advisory Role: Amgen, Janssen-Cilag, Takeda, Bristol Myers Squibb, Beigene Meral BeksacConsulting or Advisory Role: Amgen, Janssen, Sanofi, Oncopeptides, TakedaTravel, Accommodations, Expenses: Amgen, Janssen, Takeda, Sanofi Meral BeksacConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, Takeda, Sanofi Pasteur, OncopeptidesSpeakers' Bureau: Amgen, Celgene, Janssen-Cilag, Sanofi Pasteur Heinz LudwigConsulting or Advisory Role: Amgen, Janssen-Cilag, Sanofi, Seattle GeneticsSpeakers' Bureau: Celgene, Bristol Myers Squibb, Janssen-Cilag, Amgen, TakedaResearch Funding: Takeda, Amgen Sonja ZweegmanConsulting or Advisory Role: Janssen-Cilag, Takeda, Celgene, Sanofi, OncopeptidesResearch Funding: Janssen-Cilag, Takeda, CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Takeda, Celgene Elena ZamagniHonoraria: Janssen-Cilag, Celgene, Amgen, Bristol Myers Squibb, Takeda, GlaxoSmithKline, Oncopeptides, SanofiConsulting or Advisory Role: Celgene, Janssen-Cilag, Amgen, SanofiTravel, Accommodations, Expenses: Janssen-Cilag, Celgene, Amgen Ruth WesterHonoraria: Sanofi Roman HajekConsulting or Advisory Role: Takeda, Amgen, Celgene, AbbVie, BMS, PharmaMar, Janssen-Cilag, NovartisSpeakers' Bureau: Takeda, AmgenResearch Funding: Novartis, BMS, Amgen, Celgene, Takeda Lucia PantaniHonoraria: Celgene, Janssen, Takeda, Amgen Francesca GayHonoraria: Amgen, Bristol Myers Squibb, Celgene, Takeda, AbbVie, Janssen, GlaxoSmithKlineConsulting or Advisory Role: AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Oncopeptides, Roche, Takeda, Janssen, Bluebird bio Stefania OlivaHonoraria: Amgen, Celgene/Bristol Myers Squibb, JanssenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, Amgen, Takeda Vincent van de VeldenResearch Funding: BD Biosciences, Pfizer, Janssen, Novartis/Navigate, Agilent/DAKOPatents, Royalties, Other Intellectual Property: Patent EuroFlow MRD antibody tubes. No financial relationship KaLung WuConsulting or Advisory Role: Janssen Oncology Gerard BosEmployment: CiMaasLeadership: CiMaasStock and Other Ownership Interests: CIMaasHonoraria: CiMaas Mark-David LevinHonoraria: AbbVie, Celgene, Janssen, TakedaTravel, Accommodations, Expenses: Takeda, Janssen Annemiek BroijlHonoraria: Amgen, Sanofi, Celgene, Bristol Myers Squibb/Celgene, JanssenTravel, Accommodations, Expenses: Bristol Myers Squibb/Celgene Monique MinnemaConsulting or Advisory Role: Janssen-Cilag, Alnylam, Gilead SciencesSpeakers' Bureau: Celgene/Bristol Myers SquibbTravel, Accommodations, Expenses: Celgene Anders WaageHonoraria: Janssen OncologySpeakers' Bureau: Janssen Oncology Cecilie BlimarkHonoraria: Bristol Myers Squibb/Celgene, Janssen, Takeda, AmgenConsulting or Advisory Role: Adaptive Biotechnologies, Janssen, GlaxoSmithKline Niels W. C. J. van de DonkConsulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, BayerSpeakers' Bureau: Janssen Research & Development, Celgene, Amgen, Bristol Myers SquibbResearch Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis Massimo OffidaniHonoraria: BMS, Janssen, CelgeneConsulting or Advisory Role: Janssen Giuseppe A. PalumboConsulting or Advisory Role: Novartis, Janssen Oncology, AOP Orphan Pharmaceuticals, AbbVie, AstraZeneca, Celgene/Bristol Myers SquibbSpeakers' Bureau: Novartis, Celgene/Bristol Myers Squibb, AbbVieTravel, Accommodations, Expenses: Takeda, Novartis Andrew SpencerHonoraria: Janssen-Cilag, BMSConsulting or Advisory Role: Janssen-Cilag, BMSSpeakers' Bureau: Janssen-CilagResearch Funding: Janssen-Cilag Mario BoccadoroHonoraria: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, AbbVieConsulting or Advisory Role: Janssen, GlaxoSmithKlineResearch Funding: Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, Mundipharma Michele CavoHonoraria: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesConsulting or Advisory Role: Janssen, Bristol Myers Squibb, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm Therapeutics, Adaptive BiotechnologiesSpeakers' Bureau: Janssen, CelgeneNo other potential conflicts of interest were reported.

Real world evidence is important since most patients cannot be included in randomized clinical trials (RCTs). In a nationwide, cohort of relapsed/refractory multiple myeloma patients treated with daratumumab (N = 635), we retrospective studied patients treated with carfilzomib (N = 251). Data were collected by audit of medical records. We compared characteristics of patients treated with carfilzomib before daratumumab (Car-Da; N = 150) and after daratumumab (Da-Car; N = 101) with those not treated with carfilzomib (N = 384). Furthermore, we examined effectiveness and safety of carfilzomib. The group of patients treated with carfilzomib differed from patients not treated with carfilzomib in the following parameters: They were younger, more were treated up-front with high dose melphalan and autologous stem cell transplantation (HDM-ASCT)and had relapse within 18 months thereafter, and more had high-risk cytogenetic abnormalities (CA) and amplification 1q (amp1q). In patients treated with Car-Da, 30.3% had high-risk CA and 30.1% had amp1q and in Da-Car it was 43.3% and 41%, respectively. In the Car-Da cohort, 34.4% experienced early relapse after HDM-ASCT versus 47.4% in the Da-Car cohort. The percentage of patients with very good partial remission was higher in patients treated with Car-Da compared to Da-Car (31.7% vs. 17.4%). The median duration of treatment and time to next treatment (TNT) of Car-Da/Da-Car were 4.6/4.3 months and 7.1/4.3 months and only a trend toward superior TNT for Car-Da was found (p = 0.06). Toxicity of carfilzomib was the same as reported in RCT. A similar poor TNT of daratumumab was found when used before (5.6 months) or after carfilzomib (4.9 months). In this cohort of patients with sequential treatment with carfilzomib and daratumumab or vice versa, a high percentage of patients were high-risk by CA, amp1q, and early relapse after HDM-ASCT. Outcome of Car-DA and outcome of Da-Car were equally poor. These patients should be considered for new promising treatment strategies., (© 2021 John Wiley & Sons Ltd.)

Aim: To estimate current real-world costs of drugs and supportive care for the treatment of multiple myeloma in a tax-based health system. Methods: Forty-one patients were included from a personalized medicine study (2016-2019). Detailed information was collected from patient journals and hospital registries to estimate the total and mean costs using inverse probability weighting of censored data. Results: Total observed (censored) costs for the 41 patients was €8.84 million during 125 treatment years, with antineoplastic drugs as the main cost driver (€5.6 million). Individual costs showed large variations. Mean 3-year cost per patient from first progression was €182,103 (€131,800-232,405). Conclusion: Prediction of real-world costs is hindered by the availability of detailed costing data. Micro-costing analyses are needed for budgeting and real-world evaluation of cost-effectiveness.

Background: Paraneoplastic cerebellar degeneration (PCD) is a classic neurological syndrome where the presence of Anti-Tr/DNER antibodies is strongly associated with Hodgkin Lymphoma (HL). Awareness of the syndrome is important because with prompt treatment the prognosis of HL is good. The diagnosis can be a challenge in some patients. The importance of PCD in the detection of a cancer relapse is not clarified. We report the case of a 76-year-old man where a PCD, initially misdiagnosed as a stroke led to a diagnosis of a very late relapse of HL after 12 years., Case Presentation: A 76-year-old male with a 3-week history of unstable walking, slow speech and dizziness was admitted to our stroke unit apparently because the symptoms started acutely. With a diagnostic delay of 3-4 weeks a correct diagnosis of relapse HL was made based on cerebrospinal fluid changes with a strong positive reaction to anti-Tr/DNER antibodies, FDG-PET/CT scan, and biopsy findings. The medical history revealed that the patient had been diagnosed with HL previously, but has been in complete remission for 12 years. The patient was treated with intravenous immunoglobulin, chemo- and radiation therapy. Over the following 6-8 weeks he improved., Conclusions: Late relapse in HL is very rare. If it occurs it presents as a symptomatic lymphadenopathy. Our case shows, that PCD can be the only presenting symptom of a very late relapse of HL. Paraneoplastic neurological syndromes (PNS) should be considered even in patients with very long cancer remission. PCD can in rare cases mimic a stroke within the posterior circulation. If MR imaging in severe acute/subacute cerebellar syndrome is normal further investigation is mandatory to rule out a PNS, particular in patients with a previous cancer.

High proportion of patients with multiple myeloma suffer from comorbidities which may alter clinical management. Therefore, our aims were to evaluate the prevalence of comorbidities and their impact on survival. We included patients diagnosed with multiple myeloma 1990-2013 in Sweden and all diagnoses from each patient from 1985. A total of 13 656 patients with multiple myeloma were included in the study, thereof 7404 (54%) had comorbidity at diagnosis. The risk of death was increased for those with one comorbidity at diagnosis compared to those without any comorbidity (hazard ratio = 1.19; 95% confidence interval:1.14-1.25); this risk was higher for those with two (1.38; 1.30-1.47) and three or more comorbidities (1.72; 1.62-1.83). Furthermore, the risk of death was increased in patients with prior history of cancer, arrhythmia, heart failure, diabetes mellitus, cerebrovascular disease, chronic lung disease, psychological disease, peptic ulcer, neurological disease, peripheral vascular disease, chronic kidney disease, dementia, and inflammatory bowel disease. This large study shows that over 50% of multiple myeloma patients have a comorbidity at diagnosis and survival decreased with increasing numbers of comorbidities. This emphasizes the importance of comorbidities when evaluating patients and deciding on treatment strategies for individuals with multiple myeloma., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Multiple myeloma (MM) and its precursor condition, monoclonal gammopathy of undetermined significance (MGUS) have an increased risk of thrombotic events, especially during anti-myeloma treatment. Many different underlying causes for this hypercoagulability have been suggested, but current techniques to identify abnormalities in these patients are sparse and inefficient. The aim of this study was to assess the hypercoagulability in MGUS and MM patients through various coagulation analyses and identify changes in the MM patients throughout their treatment regimen., Materials and Methods: Platelet-free plasma from 38 MM patients, 19 MGUS patients and 34 healthy controls were tested for hypercoagulability using calibrated automated thrombogram, a procoagulant phospholipid assay, a microvesicle-associated (MV) tissue factor (TF) assay, and a cell-free deoxyribonucleic acid (cf-DNA) assay as a surrogate measurement for neutrophil extracellular traps (NETs)., Results: MGUS and MM patients both had elevated thrombin generation and procoagulant phospholipid activity in comparison to the control subjects. MM, and partly MGUS, showed increased MV-TF activity, however, only MM had increased levels of the cf-DNA., Conclusions: Here we demonstrated that hypercoagulability was present in patients with MGUS and MM through increased thrombin generation, possibly due to higher TF and procoagulant phospholipids (PPL) activity. This may be associated to MVs and, for MM patients, be attributed to procoagulant NETs activity; however, this remains to be determined., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In 2019 the UK Myeloma Research Alliance introduced the Myeloma Risk Profile (MRP) for prediction of outcome in patients with newly diagnosed multiple myeloma (MM), ineligible for autologous stem cell transplantation. To validate the MRP in a population-based setting we performed a study of the entire cohort of transplant ineligible MM patients above 65 years in the Danish National MM Registry. Our data confirmed the value of the MRP. In a cohort of 1,377 patients, the MRP score separated patients into three distinct risk-groups with an observed hazard ratio of 2.91 for early death in high-risk versus low-risk patients., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

This review summarises the work-up of patients with monoclonal gammopathy of undetermined significance (MGUS). In persons above 70 years of age, around 5% have MGUS, a premalignant state with a monoclonal plasma immunoglobulin or light chain (M protein) in blood and/or urine. Continuous follow-up is recommended due to a risk of malignant progression of around 1% per year. Immunoglobulin M MGUS primarily progresses to Waldenström's macroglobulinaemia, whereas non-immunoglobulin M MGUS typically progresses to multiple myeloma or amyloid light-chain amyloidosis. Treatment is unnecessary unless in rare cases of severe non-malignant complications. Screening is not advised.

Purpose: The quality of patient-reported outcome (PRO) data can be compromised by non-response (NR) to scheduled questionnaires, particularly if reasons for NR are related to health problems, which may lead to unintended bias. The aim was to investigate whether electronic reminders and real-time monitoring improve PRO completion rate., Methods: The population-based study "Quality of life in Danish multiple myeloma patients" is a longitudinal, multicentre study with consecutive inclusion of treatment-demanding newly diagnosed or relapsed patients with multiple myeloma. Education of study nurses in the avoidance of NR, electronic reminders, 7-day response windows and real-time monitoring of NR were integrated in the study. Patients complete PRO assessments at study entry and at 12 follow-up time points using electronic or paper questionnaires. The effect of the electronic reminders and real-time monitoring were investigated by comparison of proportions of completed questionnaires before and after each intervention., Results: The first 271 included patients were analysed; of those, 249 (85%) chose electronic questionnaires. Eighty-four percent of the 1441 scheduled PRO assessments were completed within the 7-day response window and 11% after real-time monitoring, achieving a final PRO completion rate of 95%. A significant higher proportion of uncompleted questionnaires were completed after the patients had received the electronic reminder and after real-time monitoring., Conclusions: Electronic reminders and real-time monitoring contributed to a very high completion rate in the study. To increase the quality of PRO data, we propose integrating these strategies in PRO studies, however highlighting that an increase in staff resources is required for implementation.

Multiple myeloma (MM) patients have increased risk of developing venous thromboembolism, but the underlying mechanisms and the effect on the coagulation system of the disease and the current cancer therapies are not known. It is possible that cancer-associated extracellular vesicles (EV), carrying tissue factor (TF) and procoagulant phospholipids (PPL) may play a role in thrombogenesis. The aim of this study was to perform an in-depth analysis of procoagulant activity of small and large EVs isolated from 20 MM patients at diagnosis and after receiving first-line treatment compared with 20 healthy control subjects. Differential ultracentrifugation at 20,000 × g and 100,000 × g were used to isolate EVs for quantitative and phenotypical analysis through nanoparticle tracking analysis, Western blotting and transmission electron microscopy. The isolated EVs were analyzed for procoagulant activity using the calibrated automated thrombogram technique, a factor Xa-based activity assay, and the STA Procoag-PPL assay. In general, MM patients contained more EVs, and immunoelectron microscopy confirmed the presence of CD9- and CD38-positive EVs. EVs in the 20,000 × g pellets from MM patients exerted procoagulant activity visualized by increased thrombin generation and both TF and PPL activity. This effect diminished during treatment, with the most prominent effect observed in the high-dose chemotherapy eligible patients after induction therapy with bortezomib, cyclophosphamide, and dexamethasone. In conclusion, the EVs in patients with MM carrying TF and PPL are thus capable of exerting procoagulant activity., Competing Interests: The authors have declared that no competing interests exist.

Objectives: The Danish Myeloma Study Group initiated a randomized, placebo-controlled, double-blinded phase II study to investigate the efficacy of adding clarithromycin to cyclophosphamide-bortezomib-dexamethasone (VCD) induction therapy in transplant eligible, newly diagnosed multiple myeloma patients. The study was prematurely terminated due to severe complications, and no effect of adding clarithromycin was found. The aim of this study was to compare health-related quality of life (HRQoL) between the two groups and to explore the coherence hereof with adverse event (AE) registration by clinicians., Methods: Patients completed three validated HRQoL questionnaires at inclusion, before cyclophosphamide priming, and two months after high-dose therapy (HDT). The mean score difference was interpreted by clinically relevant differences between groups. Spearman's correlation analysis was used to compare patient-reported toxicities with AEs., Results: Of 58 included patients, 55 participated in the HRQoL reporting. Before cyclophosphamide priming, patients in the clarithromycin group reported clinically relevant reduced HRQoL for eleven domains with persistent reduction in four domains two months after HDT. Poor correlation between patient-reported toxicities and clinician-reported AEs was observed., Conclusions: Despite the premature study termination, our data demonstrate impaired HRQoL when clarithromycin was added to the VCD regimen. We found clear underreporting of toxicities by clinicians. ClinicalTrials.gov number NCT02573935., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib-cyclophosphamide-dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy., Methods: Patients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo., Results: The study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5-64.7) and in 16 patients (51.6%, 33.1-69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group., Conclusion: The study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy. Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9).

To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005-2012 period were identified in the Danish National Multiple Myeloma Registry. For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1.4 (1.1-1.7). The registration of comorbidity was highly increased within the year preceding diagnosis of multiple myeloma (OR 3.0 [2.5-3.5]), which was attributable to an increased registration of various diseases, in particular, renal disease with OR 11.0 (8.1-14.9). The median follow-up time from diagnosis of multiple myeloma for patients alive was 4.3 years (interquartile range 2.4-6.3). Patients with registered comorbidity had increased mortality compared with patients without comorbidity, hazard ratio 1.6 (1.5-1.8). Multiple myeloma patients have increased comorbidity compared with the background population, in particular during the year preceding the diagnosis of myeloma., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aim: The Danish National Multiple Myeloma Registry (DMMR) is a population-based clinical quality database established in January 2005. The primary aim of the database is to ensure that diagnosis and treatment of plasma cell dyscrasia are of uniform quality throughout the country. Another aim is to support research. Patients are registered with their unique Danish personal identification number, and the combined use of DMMR, other Danish National registries, and the Danish National Cancer Biobank offers a unique platform for population-based translational research., Study Population: All newly diagnosed patients with multiple myeloma (MM), smoldering MM, solitary plasmacytomas, and plasma cell leukemia in Denmark are registered annually; ~350 patients. Amyloid light-chain amyloidosis, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), monoclonal gammopathy of undetermined significance and monoclonal gammopathy of undetermined significance with polyneuropathy have been registered since 2014., Main Variables: The main registered variables at diagnosis are patient demographics, baseline disease characteristics, myeloma-defining events, clinical complications, prognostics, first- and second-line treatments, treatment responses, progression free, and overall survival., Descriptive Data: Up to June 2015, 2,907 newly diagnosed patients with MM, 485 patients with smoldering MM, 64 patients with plasma cell leukemia, and 191 patients with solitary plasmacytomas were registered. Registration completeness of new patients is ~100%. A data validation study performed in 2013-2014 by the Danish Myeloma Study Group showed >95% data correctness., Conclusion: The DMMR is a population-based data validated database eligible for clinical, epidemiological, and translational research., Competing Interests: The authors report no conflicts of interest in this work.

Several risk scores for disease progression in patients with smoldering multiple myeloma (SMM) have been proposed; however, all have been developed using single-center registries. To examine risk factors for time to progression (TTP) to multiple myeloma (MM) for SMM, we analyzed a nationwide population-based cohort of 321 patients with newly diagnosed SMM registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥30 g/L and immunoparesis significantly influenced TTP (HR 2.7, 95%CI (1.5;4.7), P = 0.001, and HR 3.3, 95%CI (1.4;7.8), P = 0.002, respectively). High free light chain (FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra high-risk of transformation to MM. Using only immunoparesis and M-protein ≥30 g/L, we created a scoring system to identify low-, intermediate-, and high-risk SMM. This first population-based study of patients with SMM confirms that an M-protein ≥30 g/L and immunoparesis remain important risk factors for progression to MM., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: In multiple myeloma, heparanase (HSPE) is involved in myeloma cell growth, angiogenesis, osteoclastogenesis and shedding of syndecan-1, a key player in myeloma pathophysiology. Different single nucleotide polymorphisms (SNPs) in the HSPE gene with effect on gene function have been described, and some are associated with haematological malignancies., Methods: In this study, we evaluated four SNPs rs11099592, rs4364254, rs4693608 and rs6535455 in the HSPE gene in 348 newly diagnosed multiple myeloma patients with focus on bone morbidity (lytic bone disease and vertebral fractures) and outcome after high-dose chemotherapy with stem cell support (HDT)., Results: We observed that homozygous carriers of the rs4693608 wild-type A-allele had a higher frequency of vertebral fractures compared to carriers of the variant G-allele, P = 0.02. In multivariate analysis, homozygous carriers of the rs6535455 variant T-allele had a longer survival than homo- and heterozygous carriers of the wild-type C-allele, hazard ratio 0.3 (95% CI 0.1-0.7, P = 0.002)., Conclusion: The SNPs rs4693608 and rs6535455 in the HSPE gene may influence bone morbidity and outcome in multiple myeloma. Our results are an interesting observation but can be chance findings and need confirmation in studies exploring the functional role of SNPs in the HSPE gene in multiple myeloma., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; light-chain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenström's macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance., (Copyright© Ferrata Storti Foundation.)

Objective: To estimate the positive predictive value (PPV) and completeness of the monoclonal gammopathy of undetermined significance (MGUS) diagnosis coding in a hospital registry within a population-based health-care setting., Patients and Methods: Through the Danish National Patient Registry (DNPR), we identified 627 patients registered with MGUS in two Danish regions during the period January 2001-February 2011. We reviewed the medical records of all patients registered with MGUS at the Department of Hematology, Aalborg University Hospital, and a sample of patients registered at the other three hematological departments in the two regions. We estimated the PPV of the MGUS diagnosis based on this sample of 327 medical records. We also estimated the completeness of the DNPR by linking data from the DNPR and data from a previously validated MGUS cohort of 791 patients identified through the laboratory system covering North Jutland Region., Results: The diagnosis of MGUS was confirmed in 231 patients and assessed as probable in an additional 38 patients, corresponding to a PPV of 82.3% (95% confidence interval [CI] 78.1%-86.4%). By contrast, 58 (17.7%) of the patients did not definitively meet the diagnostic criteria for MGUS. When we excluded patients registered with malignant monoclonal gammopathy recorded prior to or within the first year after registration of MGUS in the DNPR, the PPV increased to 88.3% (95% CI 84.5%-92.1%). The DNPR only registered a diagnosis of MGUS in 133 of the 791 MGUS patients identified through the laboratory system, corresponding to a completeness of 16.8% (95% CI 14.1%-19.6%)., Conclusion: The PPV of the diagnosis coding for MGUS in the DNPR is high and can be further improved by simple data restriction. However, the low completeness raises concern that MGUS patients registered in the hospital system may be highly selected.

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.

Vascular endothelial growth factor (VEGF) is a potent proangiogenic factor. Several single nucleotide polymorphisms (SNPs) in the VEGF gene with influence on VEGF expression have been described. In multiple myeloma, VEGF stimulates angiogenesis which is correlated with disease progression and prognosis. In this study, we evaluated the association between genetic variations in the VEGF gene in patients with multiple myeloma and time to treatment failure (TTF) after high-dose melphalan and stem cell support (HDT), overall survival (OS) and efficacy of the anti-angiogenic drug thalidomide. Retrospectively, the SNPs -2,578C>A (rs699947), -460C>T (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) in the VEGF gene were examined in 348 patients with newly diagnosed multiple myeloma initially treated with HDT, where 176 patients were treated with thalidomide at relapse. None of the examined geno- or haplotypes was associated with differences in TTF after initial therapy or OS. A possible relation between the haplotype -2,578A/-460C/+405G (ACG) and effect of thalidomide was seen. Patients with no copies of the haplotype ACG had a longer time to next treatment than patients with one or two copies of the haplotype ACG, median 13.7 months vs. 9.2 months, p=0.007. In conclusion, the haplotype ACG in the VEGF gene may influence the efficacy of thalidomide in multiple myeloma. Further analyses are needed to confirm these findings and get insight into the functional effect of these polymorphisms, so in the future we may be able to select multiple myeloma patients who especially will benefit from treatment with thalidomide., (Copyright © 2011 UICC.)

Little is known on the impact of polymorphisms in the IL1B gene on outcome in multiple myeloma. In a population-based study of 348 Danish myeloma patients treated with high-dose treatment (HDT), 146 patients treated with INF-α maintenance treatment, and in 243 patients with relapse, we analysed the impact on outcome of HDT, INF-α maintenance treatment, and treatment with thalidomide and bortezomib at relapse, in relation to the major identified functional polymorphisms in the promoter region of IL1B. The wild-type C-allele of IL1B C-3737T and non-carriage of the IL1B promoter haplotype TGT (-3737(T), -1464(G) and -31(T)), giving high IL1B promoter activity, were associated with longer time-to-treatment failure (TTF) (HR, 1.4 (1.0-1.9) and 1.5 (1.1-2.0)) and overall survival (HR, 1.8 (1.2-2.6) and 1.6 (1.1-2.3)) after HDT. Among INF-α treated patients, a trend towards better TTF was found in patients carrying the wild-type C-allele of IL1B C-3737T (HR, 1.6 (1.1-2.4)). Furthermore, among INF-α treated patients, gene-gene interaction studies on IL1B C-3737T and NFКB1-94ins/del ATTG revealed a fourfold increase in TTF for homozygous carriers of wild-type alleles at both loci as compared to variant allele carriers at both loci. No relation to genotype and outcome was found for relapse patients treated with thalidomide or bortezomib. Our results indicate that a subpopulation of myeloma patients carrying the wild-type C-allele of IL1B C-3737T and non-carriers of the promoter haplotype TGT (-3737(T), -1464(G) and -31(T)) benefit from a better outcome of HDT and INF-α treatment, an effect that may be related to the NF-κB pathway.

The gene RAI was originally described as an inhibitor of RelA/p65 subunit of nuclear factor κB (NF-κB). Here, we analyse the association between genetic variation in the genes RAI and CD3EAP and outcome of 348 myeloma patients treated with high-dose treatment (HDT), 146 patients treated with interferon-α (INF-α) as maintenance treatment, 177 patients treated with thalidomide, and 74 patients treated with bortezomib at relapse and address if the effects of polymorphisms in CD3EAP and RAI are modified by a functional polymorphism in NFКB1. By linkage disequilibrium mapping, we found that variant alleles of several polymorphisms in a sub-region of 19q13.3 spanning the regions RAI-intron1-1 to RAI intron1-3 and the region exon1 to exon3–6 in CD3EAP were associated with prolonged time-to-treatment failure (TTF; p = 0.003) and overall survival (OS; p = 0.02). Haplotype analyses revealed that none of the haplotypes were more strongly associated to TTF or OS than the two strongly linked SNPs, RAI-intron1-1 (rs4572514) and CD3EAP G-21A (rs967591). The association of RAI-intron1-1 and CD3EAP G-21A with TTF was independent of NFKB1-94 ins/del, but homozygous ins-allele carriers which were also variant allele carriers of RAI-intron1-1 or CD3EAP G-21A had the longest OS. Among patients treated with INF-α or thalidomide, no effect was seen in relation to genotype. Our results indicate that polymorphism in RAI and CD3EAP are associated with outcome of myeloma patients treated with HDT. Combination analyses with the functional polymorphism in NFKB1 suggest that a possibly functional effect of RAI or CD3EAP could be related to NF-κB availability.

Background: Patients with multiple myeloma are at increased risk of venous thromboembolism (VTE), but little information is available on VTE risk in patients with the precursor condition monoclonal gammopathy of undetermined significance (MGUS)., Objective: To evaluate the risk of VTE and its impact on mortality in patients with MGUS., Patients and Methods: We identified 1610 patients with MGUS and no prior diagnosis of VTE during the 1978-2005 period in North Jutland County, Denmark. We used the Danish Central Population Registry to select 16,100 general population comparison cohort members with no prior VTE diagnosis, matched with the MGUS patients by age, sex, and comorbidity. Follow-up data on VTE incidence in the two groups were obtained from the Danish National Patient Registry covering all Danish hospitals. Time-varying Cox regression analysis was used to compute the incidence rate ratio (IRR) of VTE and the mortality rate ratio (MRR) for MGUS patients who developed VTE compared to MGUS patients without VTE., Results: In the MGUS cohort, 50 VTE events were identified during 12,594 person-years (PY) of follow-up, corresponding to an incidence rate of 4.0 VTEs/1000 PY. The IRR for VTE among MGUS patients compared to the comparison cohort was 1.37 (95% confidence interval (CI): 1.00-1.88). Of the 50 MGUS patients with VTE, one was later diagnosed with malignant transformation. The adjusted MRR for MGUS patients with VTE compared to MGUS patients without VTE was 1.94 (95% CI: 1.36-2.77)., Conclusions: MGUS is a risk factor for VTE, and VTE is a marker for increased mortality among MGUS patients., (© 2010 John Wiley & Sons A/S.)

Good's syndrome (GS) is a rare immunodeficiency complicating thymoma and characterized by absence of B-cells, hypogammaglobulinaemia and a reduced CD4 T-cell level. Autoimmune neutropenia coexisting with GS is very unusual and carries a poor prognosis due to severe immunodeficiency. We report a case of a thymoma patient with GS and autoimmune neutropenia. Neutropenia disappeared on filgrastrim, prednisone and azathioprine treatment. However, the patient still suffers from GS and requires regular prophylactic immunoglobulin injections. On this treatment, the patient has survived for nine years.

Introduction: It is unknown whether a prior diagnosis of monoclonal gammopathy of undetermined significance (MGUS) affects cancer survival., Design and Methods: We linked data on 1652 cases of MGUS diagnosed during 1978-2006 in North Jutland County, Denmark with the Danish Cancer Registry and the National Patient Registry to obtain information on survival of cancer patients with a previous MGUS compared with that of cancer patients without MGUS, matched on cancer type, age, sex and year of diagnosis. Stratified Cox regression analysis was used to compute mortality rate ratios controlling for the matching factors and comorbidity., Results: We included 323 cancer patients with previously detected MGUS and 3154 comparison cancer patients without MGUS. The 5-year survival probability was 26.2% (95% CI, 21.2%-31.5%) in cancer patients with MGUS and 30.5% (28.8%-32.1%) in cancer patients without MGUS. The adjusted mortality rate ratio (MRR) was=0.94 (95% CI, 0.82-1.09). Survival following a diagnosis of multiple myeloma, the cancer site of main interest, did not differ according to a preceding MGUS diagnosis. Among patients with immune-related cancers (liver, cervix, malignant melanoma and non-melanoma skin cancers), a preceding MGUS diagnosis was associated with reduced survival (adjusted MRR=1.49 (95% CI: 0.96-2.31)). In contrast, for other non-haematological cancers a prior MGUS diagnosis was associated with a lower MRR (0.78 (95% CI, 0.63-0.96))., Conclusion: Our study does not indicate that previously detected MGUS is a prognostic factor for cancer survival in general., (Copyright © 2010 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Introduction: Few population-based studies exist on incidence, risk of infection and mortality in hairy cell leukaemia (HCL)., Material and Methods: We used population-based medical databases to identify 209 patients who were diagnosed with HCL in the period from January 1997 to August 2007 in Denmark. An age- and sex-matched comparison cohort of 2,090 persons was selected from the general population. We computed the incidence of HCL using demographic data. Hospitalizations with pneumonia and bacteraemia were determined from the Danish National Patient Registry. Cox regression analysis was used to estimate the relative risk (RR) of infection and mortality ratios (MRR) adjusting for age, sex and comorbidity., Results: The HCL incidence rates were 1.97 (95% confidence interval 1.51-2.53) and 5.37 (4.57-6.28) per million person-years for women and men, respectively. During a median follow-up of 4.5 years, 48 HCL patients were hospitalized with pneumonia or bacteraemia. The adjusted RR of infection was 8.04 (4.99-12.95) the first year after diagnosis and 1.17 (0.71-1.94) for the remaining follow-up period. The adjusted MRRs were 4.26 (2.61-6.96) and 1.12 (0.75-1.65) the first year after diagnosis and the remaining follow-up period, respectively., Conclusion: In the second and subsequent years after HCL diagnosis, the risk of infection and mortality was similar to that of the general population.

Background: Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma., Methods: This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883., Findings: From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group., Interpretation: Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma., Funding: Nordic Cancer Union and Novartis Healthcare., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objective: To analyse if patients with early relapse after high-dose chemotherapy with stem cell support (HDT) benefit from new treatment strategies in a population-based setting., Methods: We conducted a retrospective study of relapse treatment and survival in 348 patients undergoing HDT in Denmark in 1994-2004. Patients were divided into two groups according to time-to-treatment failure (i) within 18 months after HDT and (ii) later than 18 months after HDT. The fraction of patients surviving 3 yr after first relapse was evaluated in relation to calendar periods for introduction of new drugs: before the introduction of thalidomide (1995-1999), before the introduction of bortezomib and lenalidomide (2000-2002) and when patients had access to all treatment modalities (2003-2008)., Results: Two hundred and forty-three patients suffered from relapse which required treatment. The median follow-up time was 91.4 months (60-158.8 months) and overall survival was 56.3 months after HDT. The fraction of patients alive 3 yr after first relapse increased in the periods after the year 2000 for patients with late relapse: 1995-1999, 36%; 2000-2002, 57%; and 2003-2008, 72% (P = 0.03), in contrast to patients with early relapse: 1995-1999, 25%; 2000-2002, 33%; and 2003-2008, 31% (P = 0.7)., Conclusion: Improved survival was only observed among patients with late relapse after HDT and this may be because of increased use of salvage HDT, improved supportive care and introduction of new drugs.

Background: The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment., Methods: Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication., Results: In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib., Conclusion: There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome.

Background: Maintenance therapy with interferon-alpha after high-dose treatment with stem cell support in multiple myeloma has been intensively debated. In this study, we evaluated the response to treatment with interferon-alpha in relation to genetic variation in genes related to inflammation., Design and Methods: In a retrospective study of 296 patients with multiple myeloma undergoing high-dose therapy between 1994 and 2004, 146 patients were treated with interferon-alpha as maintenance therapy. We tested the polymorphisms IL1B T-31C, IL6 G-174C, NFKB1-94ins/delATTG, CD3EAP G-21A and PPP1R13L IVS1 A4364G for associations with time to treatment failure and overall survival with and without interferon-alpha treatment., Results: The wild type ins-allele of polymorphism NFKB1-94 ins/delATTG was, by multivariate Cox analysis, associated with longer time to treatment failure (p=0.01) and overall survival (p=0.0084) when tested between treatment arms and in the subgroup of patients treated with interferon-alpha the wild type ins-allele was associated with longer overall survival (p=0.002). In the absence of interferon-alpha treatment, there was no association between the polymorphisms and treatment outcome, except for patients homozygous for the wild type G allele of IL6 G-174C who survived longer (p= 0.0074) than variant allele carriers. There was no association between the polymorphisms IL1B T-31C, CD3EAP G-21A and PPP1R13L IVS1 A4364G and treatment outcome for interferon-alpha., Conclusions: Patients who are homozygous carriers of the wild type ins-allele of the NFKB1 -94ins/delATTG polymorphism may benefit from treatment with interferon-alpha, in contrast to patients carrying the variant allele. This result may indicate that the effect of interferon-alpha treatment is dependent on the availability of nuclear factor-kappaB and the polymorphism in NFKB1 may, therefore, be a good prognostic marker for multiple myeloma patients on maintenance treatment with interferon-alpha after high-dose therapy. A prospective study of interferon-alpha treatment in relation to NFKB1 -94ins/delATTG is highly warranted.

Bisphosphonate-associated osteonecrosis of the jaw (BON) is mainly observed in patients with multiple myeloma, and to a lesser extent in breast and prostate cancer patients receiving intravenous treatment with potent bisphosphonates. The incidence of BON increases with the duration of bisphosphonate therapy and with the potency of the used bisphosphonate. BON usually develops after tooth extraction or other oral surgery, and has proven difficult to treat. Optimal dental hygiene should be ensured prior to treatment initiation where possible, and once bisphosphonate treatment is instituted, oral surgery should be avoided if possible.

Little information is available on the risk of fractures in patients with monoclonal gammopathy of undetermined significance (MGUS). We identified 1535 patients with MGUS between 1978 and 2003 in North Jutland County, Denmark. The population control group consisted of 15 350 persons selected from the Danish Central Population Registry, matched by age and sex. Data on fractures in the two groups were obtained from the regional Hospital Discharge Registry. In the MGUS cohort, 187 first-time fractures were identified during 9754 person-years of follow-up, corresponding to an incidence rate of 19/1000 person-years. The adjusted relative risk for fractures among MGUS patients compared with population controls was 1.4 [95% confidence interval (CI), 1.2-1.6]. After 5 years of follow-up, the risk difference was 1.8% (95% CI, 0.5-3.0). Six of the 187 MGUS patients with fractures were later diagnosed with malignant transformation. Relative risks for fractures were increased in IgG-type MGUS [1.3 (95% CI,1.1-1.6)], IgM-type MGUS [1.6 (95% CI, 1.1-2.2)] and MGUS with kappa light chain [1.4 (95% CI, 1.1-1.7)]. MGUS patients had an increased risk of fractures, which could not be explained by comorbidity, advanced age, gender or malignant transformation.

Introduction: Data seem to indicate that young adults with acute lymphoblastic leukemia (ALL) have a better survival rate when treated with paediatric protocols than with adult ALL protocols. The purpose of this study was to report the clinical characteristics and outcome of all children and young adults 10-19 years of age diagnosed with ALL in Denmark between 1992 and 2001., Materials and Methods: The study included 99 patients 10-19 years of age with ALL in Denmark during a 10-year period found in the complete NOPHO (Nordic Society of Pediatric Hematology and Oncology) registry and through the Danish Cancer Registry and local pathology databases. Data were retrieved by reviewing patients' medical charts. 61 children (10-14 years) were treated on paediatric protocols, and 38 young adults (15-19 years) were diagnosed with ALL. Data were reported as of 1 January 2005., Results: There were no differences between the two groups with respect to the distribution of T-ALL, CNS leukemia, total WBC and high-risk chromosomal abnormalities. There was a statistically significant lower event-free survival rate (EFS) (p < 0.01) and lower overall survival rate (p < 0.01) in young adults than in 10-14-year-old children (0.38 vs. 0.60 and 0.47 vs. 0.67). There were more transplant-related deaths in the young adults. The higher treatment intensity in children may be an explanatory factor. Children were given more prednisone, vincristine and high-dose methotrexate than were the young adults., Conclusion: Young adult patients with ALL might benefit from therapy with paediatric NOPHO ALL protocols.

A 38-year-old diabetic woman presented with a deep venous thrombosis of the right calf muscle two weeks after an infection of the pharynx. After one week of treatment with warfarin, she was readmitted in septic shock with a massive swelling of the leg. The thrombosis had progressed to the right iliac and femoral veins, and an abscess of the iliopsoas muscle caused by group A streptococci was detected. The treatment consisted of surgical drainage, intravenous penicillin and eventually hip joint exarticulation.

Osteonecrosis of the jaws in patients on chronic bisphosphonate therapy has been reported in small series since 2003. We present two patients with multiple myeloma who developed osteonecrosis of the jaws on intravenous treatment with zolendronic acid and pamidronate, respectively. The patients were treated with debridement of the involved bone and long-term antibiotic therapy.

Background: Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms., Methods: In a population-based case-control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes., Results: Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype., Conclusions: Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.