Search

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract 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.

Summary: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article presents a population-based study of 348 myeloma patients undergoing autologous transplant. The researchers have tested functionally important polymorphisms in the P2RX7 and P2RY2 genes for association with risk of disease. Chi-square test or fisher's exact test, Kaplan-Meier method and log rank test, and cox proportional hazard analysis were used in the study.