Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of ...multiple myeloma (MM).
The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m
) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib.
Thirty-two patients, median prior therapies 4 (range, 1-8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m
, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months.
Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.
A regimen of escalating doses of thalidomide, in combination with bortezomib and high-dose melphalan (mel/vel/thal), was evaluated as a conditioning regimen for autologous stem cell transplantation ...(ASCT) in multiple myeloma (MM) patients with a prior transplant who had relapsed or achieved less than a complete remission following a prior ASCT. Thalidomide was dose escalated starting from 600 mg to 1000 mg on days -5 to -1 in a 3 × 3 design, bortezomib was administered at 1.6 mg/m
intravenously on days -4 and -1 and melphalan 200 mg/m
was administered on day -2. No dose-limiting toxicity was seen in the phase I portion of the trial. An additional 20 patients were enrolled at the maximum tolerated dose of thalidomide of 1000 mg daily. The overall response rate was 69% with 38% complete remission. Median PFS and OS were 9.3 and 65.4 months, respectively, with a median follow-up of 17.8 months. The most common grade 3-4 adverse events (AEs) were neutropenic fever (58.6%), mucositis (6.9%), and diarrhea (6.9%). Serious AEs included somnolence (13.8%) and tumor lysis syndrome (3.4%). The addition of high-dose thalidomide to bortezomib and melphalan as conditioning for salvage ASCT was well tolerated and was an effective conditioning regimen.
Acute respiratory distress syndrome (ARDS) is a disorder that involves the activation of alveolar macrophages triggering the innate immune system. The parenchymal lung injury seen in ARDS is a result ...of many proinflammatory elevations including interleukin-6. There remains no effective standard of care of ARDS, and current treatments at this time currently do not target the immunological mechanisms or pathways involved. Treatments involving this pathway should be further investigated as targeted treatment. We discuss a case of a patient with multiple myeloma who was hospitalized with drug-induced ARDS who had a rapid response to an anti-interleukin-6 monoclonal antibody.
Despite continuing advancements in novel therapeutics for multiple myeloma (MM), high-dose therapy with autologous stem cell rescue continues to represent the standard approach to treat ...transplant-eligible, newly diagnosed patients. As the disease remains essentially incurable, and median progression-free survival (PFS) times after autologous transplant are measured in years and not decades, attempts to improve outcomes in the post-transplant setting have been extensive and commonly focused on a "maintenance" approach. Although multiple trials have demonstrated PFS advantages for a variety of maintenance strategies, it is our position that the potential risks outweigh the benefits of this approach and this should not be the standard of care outside of clinical trials.
We assessed the safety, efficacy, maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D) of selinexor, a first in class oral selective inhibitor of nuclear export (100 mg once weekly ...QW or 60 mg twice weekly), in combination with daratumumab (16 mg/kg per label) and dexamethasone (40 mg QW) (SDd) in patients with relapsed refractory multiple myeloma (RRMM). Thirty‐four patients (median prior therapies, 3 range, 2‐10) were enrolled; MM was refractory to proteasome inhibitor (PI) in 85%, immunomodulatory agent (IMiD) in 76%, both in 74%, and daratumumab in 6% of patients. Two dose‐limiting toxicities (DLTs) were reported in the selinexor 60 mg twice‐weekly cohort with no DLTs in the 100 mg QW cohort, making 100 mg QW the MTD and RP2D. Common treatment‐related adverse events included thrombocytopenia (70.6%), nausea (70.6%), fatigue (61.8%), anemia (61.8%), and neutropenia (50.0%). Overall response rate was 73% and median progression‐free survival 12.5 months in daratumumab‐naïve patients. SDd was well tolerated and its promising efficacy suggests that further study of this PI‐ and IMiD‐free regimen in RRMM patients who had at least one prior line of therapy including a PI and an IMiD but whose disease is naïve to daratumumab is warranted.
The water use of societies results in multiple environmental and social impacts and is a fundamental component of sustainability. Correspondingly, water footprint studies have grown significantly in ...numbers over the last decade. However, these studies mostly account for the human appropriation of freshwater resources, while overlooking various alternative water resources. This paper responds to the growing need for a complete water footprint accounting and presents an extended framework of the blue water footprint, comprised of seven water types. A case study shows spatially-explicit and use-specific analysis of Israel's diverse water system. Israel's freshwater use accounts for only 40% of its total water use. Desalinated seawater and reused wastewater contribute 52% and 45% to the country's municipal and agricultural water use, respectively. The “original” blue water footprint assumes only freshwater use; thus, it overestimates the appropriation of natural water resources by humans. The extended blue water footprint accounts for seawater, brackish water, runoff, and reused wastewater along with surface water and fresh groundwater. It, therefore, estimates the human water use more accurately.
Alternative water types' use has some adverse environmental and health impacts. These include high energy intensity due to desalination, soil salinization from brackish water irrigation, and human exposure to traces of pharmaceutical in drinking water due to treated wastewater irrigation. By acknowledging the water mix of different sectors and regions, the extended blue water footprint contributes to advancing a water-energy nexus analysis or accounting for various environmental and health impacts of water use.
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•We propose an extended framework for blue water footprint assessment.•The extended blue water footprint includes seven types of marginal and freshwater.•Our analysis shows that only 40% of Israel's water use originates from freshwater.•The water mix depends on the scale, location, and sector being analyzed.•The extended blue water footprint is vital for analyzing environmental impacts.
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