This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4–14.4) vs 10.0 months (95% CI 7.7–12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760–1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

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The molecular mechanisms of acute lung injury (ALI) are closely associated with nucleotide-binding domains and leucine-rich repeat (NLR) pyrin domains containing 3 (NLRP3) inflammasome, in which alveolar macrophages (AMs) exert an essential function. Our study has been proved that artesunate (AS) inhibits ALI. Nevertheless, the inhibition actions of AS on activation of NLRP3 in renal ischemia-reperfusion (RIR)-mediated ALI remain to be further discussed. Male Sprague-Dawley rats were randomly assigned into four groups: sham + NS, sham + AS, RIR + NS, and RIR + AS. RIR-mediated ALI was performed through bilateral renal pedicle occlusion for 60 min followed by reperfusion for 24 h. AS (15 mg/kg) or NS was injected intraperitoneal to rat 1 h before RIR treatment. AMs were rendered hypoxic (0.5%) for 2 h and reoxygenated for 24 h. Lung injury index and histology, and inflammatory cells and cytokine release in the BALF and AMs were examined. The protein and mRNA levels of NLRP3, ASC, and caspase-1 in the lung and AMs were evaluated via Western blot and real-time RCR. In this research, we indicated that AS preconditioning inhibited RIR-mediated lung damage, vascular permeability, and edema in rats. AS reduced RIR-mediated ALI, as characterized by abatement in the count of inflammatory cells, and the production of inflammatory cytokines in the BALF. AS administration inhibited the number of F4/80-positive cells, the activity of myeloperoxidase, and the fiery cytokines mRNA expression in lung samples of RIR-stimulated rats. Furthermore, AS alleviated the activity of caspase-1 and activation of NLRP3 through depending on reactive oxygen species (ROS). An in vitro finding that AS mitigated hypoxia/reoxygenation-mediated activation of AMs partially supported in vivo study. In a word, these findings demonstrate that AS pretreatment attenuated RIR-mediated ALI potentially through reducing ROS-induced activation of the NLRP3 inflammasome.