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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.

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.

Sickle cell anemia (SCA) and multiple myeloma (MM) are debilitating hematologic diseases impacting hemoglobin and plasma cells, respectively. Despite differing origins, they share overlapping clinical features including bone pain and anemia. A cornerstone of SCA is to induce fetal hemoglobin through hydroxyurea treatment. Lenalidomide, a central treatment of MM, has also been shown to induce fetal hemoglobin in vitro. Here we present a case of a young woman with SCA and subsequently multiple myeloma. When lenalidomide was used as part of multiple myeloma treatment, we investigated the proposed induction of fetal hemoglobin, using high-pressure liquid chromatography. Over a treatment period of 114 days, we did not observe lenalidomide-induced increases in fetal hemoglobin and were thereby unable to replicate in vitro findings. Moreover, the case highlights many difficulties of diagnosing and treating patients with SCA and concurrent malignancies.

The revised international staging system (R-ISS) in multiple myeloma (MM) was recently updated as the second R-ISS (R2-ISS) and refined prognostication in clinical trial populations. By including 2929 Danish patients with MM and complete data on R2-ISS registered from 2005 through 2019, we validated the R2-ISS for overall survival (OS) in a population-based cohort; however, only partly among younger patients. We thus developed a real-world international staging system (RW-ISS) from a 75% training cohort. Feature selection and weighted scores of high-risk variables from a Cox regression model of OS included age >70 years (2 points), performance status (PS) > 1 (2 points), PS 1 (1 point), t(14;16) (1 point), ISS III (1 point), ISS II (0.5 points), high lactate dehydrogenase (0.5 points), and del(17p) (0.5 points). In the test set, patients with RW-ISS I (0–2.0 points, 38.2%), II (2.5–3.0 points, 19.8%), III (3.5–4.5 points, 27.1%), and IV (5.0–7.0 points, 15.0%) demonstrated a median OS of 9.5, 5.5, 3.4, and 1.1 years, respectively ( P  < 0.0001) and the C-index was superior for RW-ISS as compared to both R2-ISS and R-ISS (0.708 vs 0.604 vs 0.595, respectively). RW-ISS was in part externally validated. We thus recommend using RW-ISS in routine clinical care of NDMM.

Lenalidomide maintenance (LM) has shown benefit in progression‐free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high‐dose melphalan and autologous stem cell transplantation (HDM‐ASCT). In Denmark, LM has been approved and publicly funded for all patients treated with HDM‐ASCT since June 2019. Patients with newly diagnosed MM treated with their first HDM‐ASCT between June 2019 and March 2022 were included and followed until data cut‐off in June 2023. To compare outcomes, a historical pre‐LM cohort from the Danish MM Registry, consisting of 364 MM patients treated with HDM‐ASCT between June 2015 and June 2019, was used. Among 364 patients treated with HDM‐ASCT after June 2019, 22.3% received consolidation therapy and 3.7% underwent tandem HDM‐ASCT. During follow‐up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. In a 6‐month landmark analysis, early discontinuation did not negatively impact PFS or OS. The LM cohort had similar PFS, and OS compared to the pre‐LM cohort. The 3‐year PFS and OS rates in the LM cohort were 61% and 86%, respectively, while the pre‐LM cohort had a 3‐year PFS of 55% and a 3‐year OS of 89%. In conclusion, the introduction of LM as a nationwide treatment option in Denmark did not lead to improved clinical outcomes.

Mosaic chromosomal alterations (mCAs) in hematopoietic cells increase mortality and risk of hematological cancers and infections. We investigated the landscape of mCAs and their clinical consequences in 976 patients with multiple myeloma undergoing high-dose chemotherapy and autologous stem cell support (ASCT) with median 6.4 years of follow-up. mCAs were detected in the stem cell harvest product of 158 patients (16.2%). Autosomal aberrations were found in 60 patients (6.1%) and affected all chromosomes. Loss of chromosome X was found in 51 females (12.7%) and loss of chromosome Y in 55 males (9.6%). Overall survival and progression were similar between carriers of autosomal mCAs and non-carriers. In contrast, female patients with loss of the X chromosome had longer overall survival (age-adjusted[a.a.] HR 0.54, 95% CI 0.32–0.93, p  = 0.02), lower risk of progression (a.a. HR 0.55, 95% CI 0.35–0.87; p  = 0.01), and better post-transplant response (higher degree of complete response (CR) or very good partial response (VGPR)). The reason for this substantial effect is unknown. Additionally, myeloma clones in the stem cell product was confirmed by mCA analysis in the few patients with multiple mCAs ( n  = 12 patients). Multiple mCAs conferred inferior overall survival (a.a. HR 2.0, 95% CI 1.02–3.84; p  = 0.04) and higher risk of myeloma progression (a.a. HR 3.36, 95% CI 1.67–6.81; p  < 0.001), which is presumed to be driven by suspected myeloma contaminants. Highlights Mosaic chromosomal alterations (mCAs) are found in the hematopoietic cells in 16% of patients with multiple myeloma undergoing ASCT. Female patients with loss of chromosome X have a significant superior response to ASCT and improved overall survival despite being older.

Although vanA carrying Enterococcus faecium human clinical isolates have been rarely found in Hungary before 2012, they have been detected in continuously increasing numbers since then. To identify factors associated with their dissemination, we investigated the clonal relatedness and plasmids of 30 vanA carrying E. faecium isolates originating from different Hungarian healthcare institutions from 2012 to 2014. Molecular typing of the isolates ( n  = 30) was performed with pulsed-field gel electrophoresis (PFGE), multilocus sequence typing, Tn 1546 polymerase chain reaction mapping, plasmid restriction fragment length polymorphism analysis, and sequencing. A single Tn 1546 variant was detected in all of the isolates. It harbored IS 1251 in the vanS-vanH intergenic region, had an entire deletion of the transposase gene and a partial deletion of the resolvase gene, and was located on a pRUM-like plasmid. Based on PFGE, the isolates could be grouped into 13 pulsotypes. Representative strains of these pulsotypes belonged to ST17, ST18, ST80, ST117, and ST203, which are known to be part of the hospital-adapted clades. The increase in the number of vanA carrying E. faecium clinical isolates in Hungary could be explained by the dissemination of pRUM-like vancomycin resistance plasmids in hospital-adapted clonal lineages.