Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design

Although the treatment of relapsed/refractory multiple myeloma has improved dramatically over the past decade, the disease remains incurable; therefore, additional therapies are needed. Novel combination therapies incorporating monoclonal antibodies have shown significant promise. Here we describe the design of a Phase III study (NCT03275285, IKEMA), which is evaluating isatuximab plus carfilzomib and low-dose dexamethasone, versus carfilzomib/dexamethasone in relapsed/refractory multiple myeloma. The primary end point is progression-free survival. Responses are being determined by an independent review committee using 2016 International Myeloma Working Group criteria, and safety will be assessed throughout. The first patient was recruited in November 2017, and the last patient was recruited in March 2019; 302 patients have been randomized, and the study is ongoing. / Clinical trial registration: NCT0327528

Satellite-based drought assessment in the endorheic basin of Lake Balkhash

Introduction: This study investigates into the drought-prone region of the Lake Balkhash basin, conducting a thorough analysis spanning 2 decades, emphasizing its significant impact on agriculture and water challenges in Central Asia. Beyond the specific focus on this region, the research aims to contribute valuable insights that extend our understanding of the broader implications of drought in the area.Methods: Utilizing MODIS satellite imagery, the study employs the Vegetation Health Index a comprehensive indicator combining the Vegetation Condition Index and Temperature Condition Index ranging from 0 (extreme aridity) to 100 (optimal moisture). The assessment of drought conditions from 2000 to 2020 includes probabilistic mapping, trend analysis, and Pearson’s correlation coefficients. Connections with hydrological factors, such as river water levels and the Balkhash Lake area, are explored, along with in-depth analyses of land use data and the GRACE dataset on water equivalent thickness, enhancing the study’s depth and reliability.Results: Drought affected approximately 44% of the Balkhash Lake Basin during the study period, impacting both Kazakhstan and China. Severe drought episodes occurred in 2000, 2008, 2014, and 2015, highlighting the region’s vulnerability. Analysis of drought trends revealed diverse patterns: 23% exhibited an increase, 17% showed a decrease, and 60% remained stable. Correlations between drought and hydrological parameters varied among stations, with positive correlations at Kapshagay and Shelek Stations, a weak correlation at Ayagoz Station, and a significant positive correlation at Lepsy despite the elevation.Discussion: This research underscores the intricate link between drought and hydrological factors in the Balkhash Lake Basin, emphasizing the need for precise water resource management and climate adaptation. Crucial strategies include proactive monitoring, tailored interventions, and the application of probabilistic drought mapping to enhance water supply management, contributing actionable insights for sustainable practices in the region.Conclusion: This study significantly advances our understanding of drought dynamics in the Balkhash Lake Basin, recommending adaptive strategies, site-specific interventions, and sustainable water management. The findings provide a crucial foundation for informed water resource decisions in Central Asia, emphasizing the importance of region-specific approaches to address diverse challenges posed by drought

Impact of catalyst layer morphology on the operation of high temperature PEM fuel cells

Electrochemical impedance spectroscopy (EIS) is a well-established method to analyze a polymer electrolyte membrane fuel cell (PEMFC). However, without further data processing, the impedance spectrum yields only qualitative insight into the mechanism and individual contribution of transport, kinetics, and ohmic losses to the overall fuel cell limitations. The distribution of relaxation times (DRT) method allows quantifying each of these polarization losses and evaluates their contribution to a given electrocatalyst\u27s depreciated performances. We coupled this method with a detailed morphology study to investigate the impact of the 3D-structure on the processes occurring inside a high-temperature polymer electrolyte membrane fuel cell (HT-PEMFC). We tested a platinum catalyst (Pt/C), a platinum-cobalt alloy catalyst (Pt$_{3}$Co/C), and a platinum group metal-free iron-nitrogen-carbon (Fe–N–C) catalyst. We found that the hampered mass transport in the latter is mainly responsible for its low performance in the MEA (along with its decreased intrinsic performances for the ORR reaction). The better performance of the alloy catalyst can be explained by both improved mass transport and a lower ORR resistance. Furthermore, single-cell tests show that the catalyst layer morphology influences the distribution of phosphoric acid during conditioning

Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in elderly patients with relapsed multiple myeloma: IKEMA subgroup analysis

In this subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285), we evaluated efficacy and safety of the anti-CD38 monoclonal antibody isatuximab (Isa) in combination with carfilzomib-dexamethasone (Isa-Kd) versus Kd in older (≥70 years of age, n = 86) and younger (<70 years, n = 216) patients with relapsed multiple myeloma (MM). Patients received Isa 10 mg/kg intravenously weekly for 4 weeks, then every 2 weeks in the Isa-Kd arm, and approved schedule of carfilzomib (twice weekly) and dexamethasone in both study arms. Primary endpoint was progression-free survival (PFS); key secondary efficacy endpoints included rates of overall response (ORR), very good partial response or better (≥VGPR), minimal residual disease negativity (MRD–), and complete response (CR). Addition of Isa to Kd resulted in improved PFS in elderly patients (hazard ratio, 0.36 [95% CI, 0.18–0.75]) consistent with the significant PFS improvement observed in the overall IKEMA population. Treatment with Isa-Kd improved depth of response versus Kd, with higher rates of ≥VGPR (73.1% vs. 55.9%), MRD– (23.1% vs. 11.8%), and CR (38.5% vs. 23.5%). Although the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) was higher in Isa-Kd, the incidence of serious TEAEs was similar between arms. Fewer elderly patients definitively discontinued treatment due to TEAEs in Isa-Kd than Kd: 11.8% versus 23.5%. In conclusion, Isa-Kd provides a consistent benefit versus Kd in elderly patients, with a manageable safety profile, and represents a new treatment option for patients with relapsed MM, independent of age

Isatuximab plus carfilzomib and dexamethasone in relapsed multiple myeloma patients with high-risk cytogenetics: IKEMA subgroup analysis

Introduction: The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), and t(14;16)] has been linked with inferior outcomes in patients with multiple myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics. Methods: High-risk cytogenetics was assessed by central laboratory and patients were classified as high risk if abnormalities were present in ≥1 of the following: del(17p): 50% cutoff; t(4;14), and/or t(14;16): 30% cutoff. Results: Of the randomized patients, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk chromosomal abnormality. A PFS benefit was seen in favor of Isa-Kd for patients with standard-risk (HR 0.440; 95% CI 0.266–0.728) and high-risk cytogenetics (HR 0.724; 95% CI 0.361–1.451). Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd (85.7%) versus Kd (63.3%) in patients with high-risk cytogenetics; however, the incidence of serious TEAEs (64.3% vs. 66.7%) was similar. Conclusions: Isa-Kd is a new treatment option for the difficult-to-treat subgroup of patients with relapsed MM and high-risk cytogenetics

Design management: changing roles of the professions

This paper sets out to explore how recent changes in procurement in construction have affected the roles that professions play in the design process. It discusses how professions that traditionally took the role of design manager now find themselves participating within previously unforeseen contexts, working in multidisciplinary teams led by contractors and with changed responsibilities at the design stage. Supply chain members who were not previously involved during the early project phases are being engaged at the earliest phases of the project life cycle and even taking leadership roles while designers sometimes work as supply chain partners. A study of design in construction and other sectors shows that in dealing with design management issues it is critical to deepen appreciation for the unique characteristics of design and the design process. The paper argues that contractors and designers taking on design management roles in a dynamic industry seeking to explore best practice and innovative approaches to procurement and in the delivery of projects need to acquire new skills, management education and develop the necessary qualities

Application of silver in microtubular solid oxide fuel cells

In this paper, the behaviour of silver as cathode conductive material, interconnect wire, and sealing for anode lead connection for microtubular solid oxide fuel cells (µSOFC) is reported. The changes in silver morphology are examined by scanning electron microscopy on cells that had been operated under reformed methane. It is found that using silver in an solid oxide fuel cell (SOFC) stack can improve the cell performance. However, it is also concluded that silver may be responsible for cell degradation. This report brings together and explains all the known problems with application of silver for SOFCs. The results show that silver is unstable in interconnect and in cathode environments. It is found that the process of cell passivation/activation promotes silver migration. The difference in thermal expansion of silver and sealant results in damage to the glass. It is concluded that when silver is exposed to a dual atmosphere condition, high levels of porosity formation is seen in the dense silver interconnect. The relevance of application of silver in SOFC stacks is discussed

Something old, something new: historical perspectives provide lessons for blue growth agendas

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.The concept of ‘blue growth’, which aims to promote the growth of ocean economies whilst holistically managing marine socio-ecological systems, is emerging within national and international marine policy. The concept is often promoted as being novel, however, we show that, historical analogies exist which can provide insights for contemporary planning and implementation of blue growth. Using a case study approach based on expert knowledge, we identified 20 historical fisheries or aquaculture examples from 13 countries, spanning the last 40–800 years, that we contend embody blue growth concepts. This is the first time, to our knowledge, that blue growth has been investigated across such broad spatial and temporal scales. The past societies managed to balance exploitation with equitable access, ecological integrity, and/or economic growth for varying periods of time. Four main trajectories existed that led to the success or failure of blue growth. Success was linked to equitable rather than open access, innovation, and management that was responsive, holistic, and based on scientific knowledge and monitoring. The inability to achieve or maintain blue growth resulted from failures to address limits to industry growth and/or anticipate the impacts of adverse extrinsic events and drivers (e.g., changes in international markets, war), the prioritisation of short-term gains over long-term sustainability, and loss of supporting systems. Fourteen cross-cutting lessons and 10 recommendations were derived that can improve understanding and implementation of blue growth. Despite the contemporary literature broadly supporting our findings, these recommendations are not adequately addressed by agendas seeking to realize blue growth.European Commissio