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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.)

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.)

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.)

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.)

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.)

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.)

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.