Bortezomib-based triplets have been the mainstay of primary therapy for patients with newly diagnosed symptomatic myeloma (NDMM) for more than a decade. Bortezomib with dexamethasone and ...cyclophosphamide (VCD or CyBorD) has been a very popular regimen with significant activity and favorable toxicity profile, especially for patients with renal dysfunction and also in a resource poor setting. The combination of bortezomib with lenalidomide and dexamethasone (VRd) is widely used in US and many European countries, especially after the results of phase 3 studies which used this regimen as induction therapy before HDM/ASCT (IFM2009, DETERMINATION) and a prospective comparison to Rd in patients with non-immediate intent to transplant (SWOG S0777). EHA/ESMO guidelines recommend VRd (or VTD-Daratumumab) as preferable options and VCd as alternative if the other two regimens are not available; however, VCd and VRd have not been compared directly in a prospective randomized trial but only in retrospective studies, from referral centers. We aimed to compare the outcomes of patients treated with VCd or VRd in a real-world setting. The analysis included 1911 NDMM patients treated with VCd (N=1326) or VRd (N=585) with available data in the BMSG database. Initially, we compared the disease and patient characteristics of the two groups: VRd treated patients were more often >65 years (48% vs 36%, p<0.001) and had less often ISS-3 disease while VCd treated patients had more often hypercalcemia (30% vs 18%, p<0.001), eGFR<30 ml/min/1.73 m2 (26% vs 10%, p<0.001), serum LDH>ULN (27% vs 16%, p<0.001), lower platelet counts (<130 K/uL) (12% vs 6%, p=0.001), anemia (Hgb<10 gr/dl) (44% vs 36%, p=0.001), ECOG performance status (PS) 3-4 (16% vs 11%, p=0.011). HDM was used as consolidation in 52% of VCd treated vs 32% of VRd treated patients (p<0.001) while maintenance therapy after induction or consolidation was given in 46% vs 64% respectively (P<0.001). ISS stage distribution was significantly different (21%, 29% and 50% were ISS-1, -2 & -3 in VCd vs 37%, 33% & 30% for VRd treated pts, p<0.001) and high risk cytogenetics frequency was similar (22% vs 22.5%, p=0.787). Distribution to R-ISS-1, -2 & -3 stages (VCd: 8%, 77% and 15% vs 18%, 71% and 11% for VCd and VRd, respectively, p<0.001) and R2-ISS-I, -II, -III & -IV (VCd: 11.5%, 22%, 48.5%, 18% and VRd: 17.5%, 26%, 39% and 17%, p=0.009) were different. A response (≥PR) after induction with VCd and VRd was recorded in 88% and 97% of evaluable patients (N=1653) (p<0.001) with CR/VGPR in 51.5% and 69% (p<0.001). Median PFS was 31 vs 44 months (p<0.001) and 5-year OS was 63% vs 73% with VCd and VRd respectively(p<0.001). We then performed a multivariate analysis that included major prognostic factors that differed between the two groups (age, ISS-3 disease, eGFR<30, LDH, PS, HDM use, HR cytogenetics, use of maintenance): VRd was independently associated with higher probability of CR/VGPR (OR: 2.3, p<0.001), improved PFS (HR: 0.718, p=0.024) and improved OS (HR:0.61, p=0.023). In ASCT-treated patients that also received lenalidomide maintenance, 3-year PFS was 61% vs 84% (p<0.001) and 5-year OS was 79% vs 93% (p=0.003) for VCd and VRd respectively. However, the significant differences in the baseline disease and clinical characteristics between the two groups do not allow direct comparisons. In order to decrease bias, we performed an analysis in pts matched for age, country, eGFR, ISS stage, cytogenetics, HDM and maintenance use. The matched groups included 182 patients each (N=364): ORR was 90% vs 98% (p<0.001), CR/VGPR rate was 51% vs 71% (p=0.001), 3-year PFS rate was 55% vs 69% (p=0.016) and the 5-year OS was 70% with VCd vs 71% with VRd (p=0.269). In the ASCT-treated subgroup, 5-year PFS and OS were 54% vs 69% (p=0.086) and 87% vs 94% (p=0.335) for VCd vs VRd. In conclusion, VCd remains an important regimen for the management of NDMM, especially in a resource poor setting and in special circumstances, although VRD is associated with a significant reduction in the risk of primary induction failure and deeper responses. In matched analysis, VCd does not seem to be associated with significantly inferior OS compared to VRd, which is associated with better responses and longer PFS. With the implementation of new drugs, such as monoclonal antibodies, VCd backbone is a reasonable option for patients that do not have access or do not tolerate VRd or in newer combinations in the upfront setting.
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Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our ...multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.
Having found their way onto the computer screens, comics soon branched into webcomics. These kept a lot of the characteristics of print comic books, but gradually adapted new unexplored modes of ...representation. Three relatively new ‘enhancements’ to the medium of comics are presented in this article: webcomics enhanced through the use of the infinite canvas, as proposed by Scott McCloud, those enhanced with videos and/or sound, and lastly those enhanced with interactive and ludic elements. All of the mentioned push the medium of comics into new waters, and by doing so they add new layers of meaning and modify their structure based on the make-up of the implemented features. Infinite canvas manages to lift some limitations of print comics without changing the overall feel too drastically, while animated and voiced webcomics, as well as interactive or game comics, have a much higher inclination to transgress into domains of other media and transform themselves in order to accommodate and integrate these novel foreign features.
Une fois qu’elles avaient trouvé leur chemin vers les écrans d’ordinateur, les bandes dessinées ont vite suscité une branche particulière, les bandes dessinées numériques. Celles-ci conservaient bien des aspects des bandes dessinées imprimées, mais peu à peu elles ont développé de nouvelles formes de représentation. Trois types d’ « expansion » relativement nouveaux sont discutés dans cet articles : les œuvres numériques enrichies par le recours à une grille « infinie », comme chez Scott McCloud ; celles complétées par des éléments vidéo et/ou sonores ; enfin celles enrichies par des éléments ludiques et interactifs. Chacune de ces nouvelles formes élargit le potentiel du médium et ajoute de nouvelles couches de sens tout en modifiant la structure de base de l’ensemble des éléments et de leur combinaison. Les grilles infinies parviennent à dépasser certaines limites de l’imprimé, sans trop changer l’expérience fondamentale du médium, cependant que les bandes dessinées nu-mériques animées et sonorisées, puis interactives et ludiques, tendent à pousser le médium vers de tout autres formes et à se transformer elles-mêmes afin de pouvoir accueillir ces nouveaux apports.
Limited data have been published on the epidemiology and outcomes of breakthrough COVID-19 in patients with hematological malignancy (HM) after anti-SARS-CoV-2 vaccination. Adult HM who received at ...least one dose of anti-SARS-CoV-2 vaccine and diagnosed with breakthrough COVID-19 between January 2021 and March 2022 and registered in EPICOVIDEHA were included in this analysis. A total of 1548 cases were included, mainly with lymphoid malignancies (1181 cases, 76%). After viral genome sequencing in 753 cases (49%), Omicron variant was prevalent (517, 68.7%). Most of the patients received at least two vaccine doses before COVID-19 (1419, 91%), mostly mRNA-based (1377, 89%). Overall, 906 patients (59%) received specific treatment for COVID-19. After 30-days follow-up from COVID-19 diagnosis, 143 patients (9%) died. The mortality rate in patients with Omicron variant was of 7.9%, comparable to that reported for the other variants. The 30-day mortality rate was significantly lower than in the pre-vaccine era (31%). In the univariable analysis, older age (p<0.001), active HM (p<0.001), severe and critical COVID-19 (p=0.007 and p<0.001, respectively) were associated with mortality. Conversely, patients receiving monoclonal antibodies, even for severe or critical COVID-19, had a lower mortality rate (p<0.001). In the multivariable model, older age, active disease, critical COVID-19 and at least 2-3 comorbidities were correlated with a higher mortality, whereas the administration of monoclonal antibodies, alone (p<0.001) or combined with antivirals (p=0.009), was observed protective. While mortality is significantly lower than in the pre-vaccination era, breakthrough COVID-19 in HM is still associated with considerable mortality. Death rate was lower in patients who received monoclonal antibodies, alone or in combination with antivirals. EPICOVIDEHA (www.clinicaltrials.gov; National Clinical Trials identifier NCT04733729) is an international open web-based registry for patients with HMs infected with SARS-CoV-2.
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In this paper, we present an overview of freely available web applications providing online access to spoken language corpora. We explore and discuss various solutions with which the corpus providers ...and corpus platform developers address the needs of researchers who are working with spoken language. The paper aims to contribute to the long-overdue exchange and discussion of methods and best practices in the design of online access to spoken language corpora.
Patients affected by multiple myeloma (MM) have an increased risk of severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) infection and subsequent coronavirus (20)19 disease ...(COVID‐19)‐related death. The changing epidemiological and therapeutic scenarios suggest that there has been an improvement in severity and survival of COVID‐19 during the different waves of the pandemic in the general population, but this has not been investigated yet in MM patients. Here we analyzed a large cohort of 1221 patients with MM and confirmed SARS‐CoV‐2 infection observed between February 2020, and August 2022, in the EPICOVIDEHA registry from 132 centers around the world. Median follow‐up was 52 days for the entire cohort and 83 days for survivors. Three‐hundred and three patients died (24%) and COVID‐19 was the primary reason for death of around 89% of them. Overall survival (OS) was significantly higher in vaccinated patients with both stable and active MM versus unvaccinated, while only a trend favoring vaccinated patients was observed in subjects with responsive MM. Vaccinated patients with at least 2 doses showed a better OS than those with one or no vaccine dose. Overall, according to pandemic waves, mortality rate decreased over time from 34% to 10%. In multivariable analysis, age, renal failure, active disease, hospital, and intensive care unit admission, were independently associated with a higher number of deaths, while a neutrophil count above 0.5 × 109/L was found to be protective. This data suggests that MM patients remain at risk of SARS‐CoV‐2 infection even in the vaccination era, but their clinical outcome, in terms of OS, has progressively improved throughout the different viral phases of the pandemic.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The aim of the current study was to determine whether plasmapheresis in combination with chemotherapy could significantly remove free light chains (FLC) in multiple myeloma (MM) patients with acute ...kidney injury (AKI) and therefore improve renal recovery and patient survival. During the study period, 29 patients with MM and AKI presented to our unit and were treated with two different therapy modalities (plasmapheresis with chemotherapy or bortezomib). At the end of treatment, a significant decrease of FLCs was present in the group treated with plasmapheresis compared to the bortezomib group. Patients treated with plasmapheresis had similar survival compared to patients treated with bortezomib. There was a significantly higher decrease of FLCs and longer survival in patients treated with three or more plasmapheresis sessions than in patients treated with two plasmapheresis sessions. Plasmapheresis therapy still remains a useful and effective method in the treatment of AKI in MM patients. Plasmapheresis significantly reduces FLCs compared to bortezomib especially with higher number of plasma exchange sessions but it must be combined with other chemotherapy agents in order to prolong renal recovery and therefore patient survival.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we ...describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients.
This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan–Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir.
A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mortality difference in patients after nirmatrelvir/ritonavir administration.
Haematological malignancy patients were more likely to receive nirmatrelvir/ritonavir when reporting extrapulmonary symptoms or 2nd vaccine booster at COVID-19 onset, as opposed to chronic pulmonary disease and obesity. The mortality rate in patients treated with nirmatrelvir/ritonavir was lower than in patients with targeted drugs other than nirmatrelvir/ritonavir.
EPICOVIDEHA has received funds from Optics COMMIT (COVID-19 Unmet Medical Needs and Associated Research Extension) COVID-19 RFP program by GILEAD Science, United States (Project 2020-8223).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Introduction. It has been rarely reported that a laboratory test introduced so rapid and radical changes in diagnostic algorithm as is the case with the quantitative assay of free light chains of ...immunoglobulins (FLC) in serum and its role in the diagnostic algorithm of monoclonal gammopathies. Since the first description of immunoassay in year 2001 until today, new evidence has continuously been reported in the literature that confirm the clinical usefulness of this test in diagnosis, monitoring and prognosis of monoclonal plasma-proliferative diseases, especially diseases of light chains such as primary amyloidosis, light chain deposition disease (LCDD) or light chain multiple myeloma (LCMM) and nonsecretory multiple myeloma (NSMM). Recently, a commercial test has become available on the market that uses polyclonal antibodies to specific epitopes of free light chains which are hidden in the intact immunoglobulin molecules. In 2011, a commercial immunoassay was launched on the market that uses monoclonal instead of polyclonal antibodies, reducing the variability between different series of reagents and controlling excess antigen in the sample.
Aim. The aim of this study was to evaluate monoclonal versus polyclonal antibody and immunoturbidimetric versus immunonephelometric detection technology. Does different detection tehnology – besides different used antibody – contribute to greater variability in results?
Method. In this study we compared results of 40 samples measured with polyclonal antibody (The Binding Site Ltd., Birmingham, UK) and monoclonal antibody (N Latex FLC, Siemens Healthcare Diagnostics, Marburg, Germany). In other 40 samples we compared results achieved with different antibodies and different analytical platforms (Siemens Nephelometer with Roche Cobas). Results were statistically analyzed using MedCalc software.
Results. Results are shown in Table 1. Comparing all results, it is evident that there is at least proportional error when comparing different antibodies and different analytical systems. Although it is known that immunoturbidimetry is less sensitive than immunonephelometric method, greater discrepancies in results were not found. When we categorized patients as positive and negative according to manufacturer’s reference interval for kf/lf ratio, agreement between groups with different antibody and same detection technology was 63% (weighted kappa 0.30). Agreement between groups with different antibodies and different detection technology was 86% (weighted kappa 0.22). Although we have not measured the same samples when testing antibody and analytical platform, the selected analytical platform has, according to our results, no additional impact on the variability of results.
Abstract 5680. Table 1Comparison of FLC results using different antibody and different analytical platformsMethodFLC kappa polyclonal Ab Nephelometer SiemensFLC kappa monoclonal Ab Nephelometer SiemensFLC lambda polyclonal Ab Nephelometer SiemensFLC lambda monoclonal Ab Nephelometer SiemensResults (min-max)6.59-5210.006.34-1600.001.67-3010.001.00-1600.00Passing-Bablok fitintercept (95% Cl)8.2442.9255 to 14.92491.0945-1.5910 to 5.5631slope (95% Cl)0.5950.4564 to 0.78521.87981.5336 to 2.1045Correlation rs (p<0.0001)0.9110.887MethodFLC kappa polyclonal Ab Cobas RocheFLC kappa monoclonal Ab Nephelometer SiemensFLC lambda polyclonal Ab Cobas RocheFLC lambda monoclonal Ab Nephelometer SiemensResults (min-max)2.40-453.201.10-342.002.30-452.1010.30-301.20Passing-Bablok fitintercept (95% Cl)2.622-3.8207 to 9.30230.1585-3.9731 to 4.5892slope (95% Cl)1.51.2972 to 1.99330.74160.6174 to 0.8708Correlation rs (p<0.0001)0.8730.929
Conclusion. Physicians and especially clinical biochemists must be aware of the technical shortcomings of this test, such as the variability between different series (lots) reagents, non-linearity, unreliable detection of excess antigen and overestimation of FLC concentrations due to nonspecific interference or polymerization.
Although initial results are not discouraging, it will be necessary to collect much more evidence, especially bearing in mind that use of monoclonal antibodies along with advantages has certain disadvantages. In the future, it will probably be necessary to incorporate into the guidelines a recommendation to report the method used, like for other tumor markers.
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NUK, OILJ, SAZU, SBCE, UL, UM, UPCLJ, UPUK
Background: The outcome of patients with simultaneous diagnosis of haematological malignancies (HM) and COVID-19 is unknown and there are no specific treatment guidelines. Methods: We describe the ...clinical features and outcome of a cohort of 450 patients with simultaneous diagnosis of HM and COVID-19 registered in the EPICOVIDEHA registry between March 2020 to February 2022. Results: Acute leukaemia and lymphoma were the most frequent HM (35.8% and 35.1%, respectively). Overall, 343 (76.2%) patients received treatment for HM, which was delayed for longer than one month since diagnosis in 57 (16.6%). An overall response rate was observed in 140 (40.8%) patients after the first line of treatment. After a median follow-up of 35 days, overall mortality was 177/450 (39.3%); 30-day mortality was significantly higher in patients not receiving HM treatment (42.1%) than in those receiving treatment (27.4%, p = 0.004), either before and/or after COVID-19, or compared to patients receiving HM treatment at least after COVID-19 (15.2%, p < 0.001). Age, severe/critical COVID-19, ≥2 comorbidities, and lack of HM treatment were independent risk factors for mortality, whereas a lymphocyte count >500/mcl at COVID-19 onset was protective. Conclusions: HM treatment should be delivered as soon as possible for patients with simultaneous diagnosis of COVID-19 and HM requiring immediate therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
