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Most patients cannot be included in randomized clinical trials. We report real-world outcomes of all Danish patients with multiple myeloma (MM) treated with daratumumab-based regimens until 1 January 2019. Information of 635 patients treated with daratumumab was collected retrospectively and included lines of therapy (LOT), hematologic responses according to the International Myeloma Working Group recommendations, time to next treatment (TNT) and the cause of discontinuation of treatment. Baseline characteristics were acquired from the validated Danish Multiple Myeloma Registry (DMMR). Daratumumab was administrated as monotherapy (Da-mono) in 27.7%, in combination with immunomodulatory drugs (Da-IMiD) in 57.3%, in combination with proteasome inhibitors (Da-PI) in 11.2% and in other combinations (Da-other) in 3.8% of patients. The median number of lines of therapy given before daratumumab was 5 for Da-mono, 3 for Da-IMiD, 4 for Da-PI, and 2 for Da-other. In Da-mono, overall response rate (ORR) was 44.9% and median time to next treatment (mTNT) was 4.9 months. In Da-IMiD, ORR was 80.5%, and mTNT was 16.1 months. In Da-PI, OOR was 60.6% and mTNT was 5.3 months. In patients treated with Da-other, OOR was 54,2% and mTNT was 5.6 months. The use of daratumumab in early LOT was associated with longer TNT (p<0.0001). Patients with amplification 1q had outcome comparable to standard risk patients, while patients with t(4;14), t(14;16) or del17p had worse outcome (p = 0.0001). Multivariate analysis indicated that timing of treatment (timing of daratumumab in the sequence of all LOT that the patients received throughout the course of their disease) was the most important factor for outcome (p<0.0001). The real-world outcomes of multiple myeloma patients treated with daratumumab are worse than the results of clinical trials. Outcomes achieved with daratumumab were best when daratumumab was used in combination with IMIDs and in early LOT. Patients with high-risk CA had worse outcomes, but patients with amp1q had similar outcomes to standard-risk patients.

The free light chain (FLC) ratio is a critical part of risk stratification for monoclonal gammopathy of undetermined significance (MGUS). Recently, revised FLC reference intervals developed using the iStopMM cohort, accounting for age and renal function, have reduced the rate of abnormal findings. Here, we examine the implications of the revision in an independent Danish MGUS cohort. Of 6993 MGUS individuals, 2641 had an abnormal FLC ratio by the original intervals, of whom 844 (32%) were reclassified as normal using the revised intervals. Reclassified individuals had no significantly increased risk of progression compared to those with a normal FLC ratio (hazard ratio (HR): 1.07, 95% confidence interval (CI) 0.74–1.57). Those with an abnormal FLC ratio by the revised reference intervals had an increased risk of progression (HR 2.23, 95% CI 1.79–2.78). Using the revised reference intervals, 490 individuals (16%) were reclassified to low-risk from a higher risk group. These individuals had a similar progression risk compared to others in the low-risk group. The findings validate the revised FLC reference intervals, enhancing prognostic accuracy and improving risk stratification to accurately identify MGUS individuals at risk of progression while reducing unnecessary classifications as high-risk.

Pomalidomide‐dexamethasone (Pd) has been a standard care treatment for relapsed and refractory multiple myeloma since 2013. However, the outcomes of Pd after exposure to CD38 antibodies are not known. Here we describe the real‐world use and efficacy of pomalidomide in a Danish, nationwide cohort of daratumumab‐exposed patients. We identified 328 patients that were treated with pomalidomide. Of these, 137 received Pd, 65 daratumumab‐pomalidomide‐dexamethasone (DPd), 43 pomalidomide‐cyclophosphamide‐dexamethasone (PCd), 19 carfilzomib‐pomalidomide‐dexamethasone (KPD), 11 pomalidomide‐bortezomib‐dexamethasone (PVd), and 52 pomalidomide in other combinations. Patients treated with Pd in this cohort had a partial response or better (≥ PR) rate of 35.8% and median time to next treatment (mTNT) of 4.9 months, almost identical to the results of previous prospective clinical trials. Although treatment with the various pomalidomide‐containing triplet regimens resulted in higher ≥ PR rates (PCd: 46.5%, PVd: 63.6%, DPd: 55.4%, KPd: 63.2%), the mTNT achieved was not significantly better than with Pd in most cases (PCD: 5.4, PVD: 5.3, DPD: 4.7 months). The exception to this was KPd (mTNT 7.4 months), but this regimen was mainly used earlier in the course of the disease (median time from diagnosis 2.3 years vs. 3.7–4.3 years). The most important predictor of outcomes was not the choice of index regimen ( p  = 0.72), but prior exposure ( p  = 0.0116). Compared to CD38 antibody‐naïve patients, triple‐class‐exposed patients achieved reduced ≥ PR rate (38.0% vs. 47.3%), shorter mTNT (4.0 vs. 5.9 months), and shorter median overall survival (12.4 vs. 24.2 months) with pomalidomide treatment.

Thalidomide and its derivatives, lenalidomide and pomalidomide (also known as IMiDs), have significantly changed the treatment landscape of multiple myeloma, and the recent discovery of cereblon (CRBN) as their direct biological target has led to a deeper understanding of their complex mechanism of action. In an effort to comprehend the precise mechanisms behind the development of IMiD resistance and examine whether it is potentially reversible, we established lenalidomide‐resistant (‐LR) and pomalidomide‐resistant (‐PR) human myeloma cell lines from two IMiD‐sensitive cell lines, OPM2 and NCI‐H929, by continuous culture in the presence of lenalidomide or pomalidomide for 4–6 months, until acquirement of stable resistance. By assessing genome‐wide DNA methylation and chromatin accessibility in these cell lines, we found that acquired IMiD resistance is associated with an increase in genome‐wide DNA methylation and an even greater reduction in chromatin accessibility. Transcriptome analysis confirmed that resistant cell lines are mainly characterized by a reduction in gene expression, identifying SMAD3 as a commonly downregulated gene in IMiD‐resistant cell lines. Moreover, we show that these changes are potentially reversible, as combination of 5‐azacytidine and EPZ‐6438 not only restored the observed accessibility changes and the expression of SMAD3, but also resensitized the resistant cells to both lenalidomide and pomalidomide. Interestingly, the resensitization process was independent of CRBN. Our data suggest that simultaneous inhibition of DNA methyl transferases and EZH2 leads to an extensive epigenetic reprogramming which allows myeloma cells to (re)gain sensitivity to IMiDs. Using a cell line model for IMiD resistance, this study shows that epigenetic resensitization with simultaneous inhibition of DNA methyl transferases and EZH2 can restore sensitivity to IMiDs. In addition to acquired IMiD resistance, this combined epigenetic therapy was also effective in myeloma cells with primary resistance to IMiDs, and thus deserves further testing in a preclinical and clinical setting.

Background Emergency departments handle a large proportion of acute patients. In 2007, it was recommended centralizing the Danish healthcare system and establishing emergency departments as the main common entrance for emergency patients. Since this reorganization, few studies describing the emergency patient population in this new setting have been carried out and none describing diagnoses and mortality. Hence, we aimed to investigate diagnoses and 1- and 30-day mortality of patients in the emergency departments in the North Denmark Region during 2014–2016. Methods Population-based historic cohort study in the North Denmark Region (580,000 inhabitants) of patients with contact to emergency departments during 2014–2016. The study included patients who were referred by general practitioners (daytime and out-of-hours), by emergency medical services or who were self-referred. Primary diagnoses (ICD-10) were retrieved from the regional Patient Administrative System. For non-specific diagnoses (ICD-10 chapter ‘Symptoms and signs’ and ‘Other factors’), we searched the same hospital stay for a specific diagnosis and used this, if one was given. We performed descriptive analysis reporting distribution and frequency of diagnoses. Moreover, 1- and 30-day mortality rate estimates were performed using the Kaplan-Meier estimator. Results We included 290,590 patient contacts corresponding to 166 ED visits per 1000 inhabitants per year. The three most frequent ICD-10 chapters used were ‘Injuries and poisoning’ (38.3% n  = 111,274), ‘Symptoms and signs’ (16.1% n  = 46,852) and ‘Other factors’ (14.52% n  = 42,195). Mortality at day 30 (95% confidence intervals) for these chapters were 0.86% (0.81–0.92), 3.95% (3.78–4.13) and 2.84% (2.69–3.00), respectively. The highest 30-day mortality were within chapters ‘Neoplasms’ (14.22% (12.07–16.72)), ‘Endocrine diseases’ (8.95% (8.21–9.75)) and ‘Respiratory diseases’ (8.44% (8.02–8.88)). Conclusions Patients in contact with the emergency department receive a wide range of diagnoses within all chapters of ICD-10, and one third of the diagnoses given are non-specific. Within the non-specific chapters, we found a 30-day mortality, surpassing several of the more organ specific ICD-10 chapters. Trial registration Observational study - no trial registration was performed.