Cardiopulmonary Exercise Physiology in AL Amyloidosis Patients with Cardiac Involvement and Its Association with Cardiac Imaging Parameters.

Background: Cardiopulmonary exercise testing (CPET) has been widely used for the functional evaluation of patients with heart failure. Patients with amyloidosis and cardiac involvement typically present with heart failure with preserved or mildly reduced ejection fraction. We sought to evaluate the use of CPET parameters in patients with AL amyloidosis for the assessment of disease severity and prognosis and their association with cardiac imaging findings. Methods: A single-center prospective analysis was conducted, which included 23 consecutive ambulatory patients with AL amyloidosis with cardiac involvement, not requiring hospitalization or intravenous diuretics. Patient evaluation included CPET, laboratory testing, echocardiography and cardiac MRI. The cohort was divided according to the presence of high-risk CPET characteristics (below median peak VO2 and above median VE/VCO2). Results: Patients with AL amyloidosis and cardiac involvement (median age was 60 years (56.5% males) had median peak relative VO2 (VO2/kg) of 17.8 mL/kg/min, VE/VCO2 slope of 39.4 and circulatory power of 2362.5 mmHg⋅mL/kg/min. Peak relative VO2 gradually declined across Mayo stages (p = 0.046) and exhibited a significant inverse correlation with NT-proBNP levels (r = −0.52, p = 0.01). Among imaging parameters, peak VO2 positively correlated with global work efficiency (r = 0.61, p < 0.001), and global work index (r = 0.45, p = 0.04). The group of patients with high-risk CPET findings showed evidence of more advanced disease, such as higher NT-proBNP levels (p = 0.007), increased septal and posterior left ventricular wall thickness (p = 0.043 and p = 0.033 respectively) and decreased global work efficiency (p = 0.027) without substantial differences in cardiac MRI parameters. In this group of patients, peak VO2 and VE/VCO2 were not associated significantly with overall survival and cardiac response at one year. Conclusion: In patients with AL amyloidosis, evaluation of exercise capacity with CPET identified a group of patients with more advanced cardiac involvement. The potential of CPET as a risk stratification tool in AL amyloidosis with cardiac involvement warrants further research

Bortezomib, Melphalan, and Dexamethasone for Light-Chain Amyloidosis

PURPOSE: Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS: This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016. RESULTS: A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION: BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis

Effect of prior treatments on selinexor, bortezomib, and dexamethasone in previously treated multiple myeloma

Therapeutic regimens for previously treated multiple myeloma (MM) may not provide prolonged disease control and are often complicated by significant adverse events, including peripheral neuropathy. In patients with previously treated MM in the Phase 3 BOSTON study, once weekly selinexor, once weekly bortezomib, and 40&nbsp;mg dexamethasone (XVd) demonstrated a significantly longer median progression-free survival (PFS), higher response rates, deeper responses, a trend to improved survival, and reduced incidence and severity of bortezomib-induced peripheral neuropathy when compared with standard twice weekly bortezomib and 80&nbsp;mg dexamethasone (Vd). The pre-specified analyses described here evaluated the influence of the number of prior lines of therapy, prior treatment with lenalidomide, prior proteasome inhibitor (PI) therapy, prior immunomodulatory drug therapy, and prior autologous stem cell transplant (ASCT) on the efficacy and safety of XVd compared with Vd. In this 1:1 randomized study, enrolled patients were assigned to receive once weekly oral selinexor (100&nbsp;mg) with once weekly subcutaneous bortezomib (1.3&nbsp;mg/m2) and 40&nbsp;mg per week dexamethasone (XVd) versus standard twice weekly bortezomib and 80&nbsp;mg per week dexamethasone (Vd). XVd significantly improved PFS, overall response rate, time-to-next-treatment, and showed reduced all grade and grade ≥ 2 peripheral neuropathy compared with Vd regardless of prior treatments, but the benefits of XVd over Vd were more pronounced in patients treated earlier in their disease course who had either received only one prior therapy, had never been treated with a PI, or had prior ASCT. Treatment with XVd improved outcomes as compared to Vd regardless of prior therapies as well as manageable and generally reversible adverse events. XVd was associated with clinical benefit and reduced peripheral neuropathy compared to standard Vd in previously treated MM. These results suggest that the once weekly XVd regimen may be optimally administered to patients earlier in their course of disease, as their first bortezomib-containing regimen, and in those relapsing after ASCT. Trial registration: ClinicalTrials.gov (NCT03110562). Registered 12 April 2017. https://clinicaltrials.gov/ct2/show/NCT03110562

Impact of minimal residual disease detection by next-generation flow cytometry in multiple myeloma patients with sustained complete remission after frontline therapy

Minimal residual disease (MRD) was monitored in 52 patients with sustained CR (≥2 years) after frontline therapy using next-generation flow (NGF) cytometry. 25% of patients initially MRD- reversed to MRD+. 56% of patients in sustained CR were MRD+; 45% at the level of 10−5; 17% at 10−6. All patients who relapsed during follow-up were MRD+ at the latest MRD assessment, including those with ultra-low tumor burden. MRD persistence was associated with specific phenotypic profiles: higher erythroblasts’ and tumor-associated monocytes/macrophages’ predominance in the bone marrow niche. NGF emerges as a suitable method for periodic, reproducible, highly-sensitive MRD-detection at the level of 10−6

Once-weekly selinexor, bortezomib, and dexamethasone versus twice-weekly bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label phase 3 trial

Background Selinexor with dexamethasone has demonstrated activity in patients with heavily pretreated multiple myeloma (MM). In a phase 1b/2 study, the combination of oral selinexor with the proteasome inhibitor (PI) bortezomib, and dexamethasone (SVd) induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. The aim of this trial was to evaluate the clinical benefit of weekly SVd versus standard bortezomib and dexamethasone (Vd) in patients with previously treated MM. Methods This phase 3, randomised, open label trial was conducted at 123 sites in 21 countries. Patients who were previously treated with one to three lines of therapy, including PIs were randomised (1:1) to selinexor (100 mg once-weekly) plus bortezomib (1·3 mg/m2 once-weekly) and dexamethasone (20 mg twice-weekly) [SVd] or bortezomib (1·3 mg/m2 twice-weekly) and dexamethasone (20 mg 4 times per week) [Vd]. Randomisation was done using interactive response technology and stratified by previous PI therapy, lines of treatment, and MM stage. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. Findings Between June 2017 and February 2019, 402 patients were randomised: 195 to SVd and 207 to Vd. Median PFS was 13·93 (95% CI 11·73–NE) with SVd versus 9·46 months (8·11–10·78) with Vd; HR 0·70, [95% CI 0·53–0·93]; P=0.0075. Most frequent grade ≥3 adverse events (SVd vs Vd) were thrombocytopenia (77 [40%] vs 35 [17%]), fatigue (26 [13%] vs 2 [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy rates (overall, 32·3% vs 47·1%; OR 0·52, [95% CI 0·35-0·79]; P=0.0010 and grade ≥2, 21·0% vs 34·3%; OR 0·50, [95% CI 0·32-0·79]; P=0.0013) were lower with SVd. There were 47 (24%) deaths on SVd and 62 (30%) on Vd. Interpretation Once-weekly SVd is a novel, effective, and convenient treatment option for patients with MM who have received 1-3 prior therapies. Funding Karyopharm Therapeutics In

Dickkopf-1 (Dkk-1) in plasma and synovial fluid is inversely correlated with radiographic severity of knee osteoarthritis patients

<p>Abstract</p> <p>Background</p> <p>Osteoarthritis (OA) is a common degenerative joint disease causing pain, stiffness, reduced motion, swelling, crepitus, and disability. Dickkopf-1 (Dkk-1) is a critical mediator of osteoblastogenesis and regulates the joint remodeling. The aim of this study was to examine plasma and synovial fluid Dkk-1 levels of patients with primary knee OA and to investigate their relationship with disease severity.</p> <p>Methods</p> <p>Thirty-five patients aged 55-83 years with knee OA and 15 healthy individuals were recruited into this study. Disease severity was determined using weight-bearing anteroposterior radiographs of the affected knee. The radiological grading of OA in the knee was performed according to the Kellgren-Lawrence grading system. Dkk-1 levels in both plasma and synovial fluid were evaluated using enzyme-linked immunosorbent assay.</p> <p>Results</p> <p>The average concentration of circulating Dkk-1 in the knee OA patients was remarkably lower than that of healthy controls (396.0 ± 258.8, 95%CI 307.1-484.9 vs 2348.8 ± 2051.5, 95%CI 1164.3-3533.3 pg/ml, p < 0.0001). Dkk-1 levels in synovial fluid were significantly lower than in paired plasma samples (58.6 ± 31.8, 95%CI 47.7-69.6 vs 396.0 ± 258.8, 95%CI 307.1-484.9 pg/ml, p < 0.001). Furthermore, both plasma and synovial fluid Dkk-1 levels were inversely correlated with radiographic severity (r = -0.78, p < 0.001 and r = -0.42, p = 0.01, respectively). Plasma Dkk-1 levels were also significantly correlated with synovial fluid Dkk-1 levels (r = 0.72, p < 0.001).</p> <p>Conclusions</p> <p>Dkk-1 levels in plasma and synovial fluid are inversely related to the severity of joint damage in knee OA. Dkk-1 could serve as a biochemical marker for determining disease severity and might play a potential role in the pathogenesis of the degenerative process of OA.</p

Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis

The transforming growth factor-β (TGF-β) signalling pathway is a key mediator of fibroblast activation that drives the aberrant synthesis of extracellular matrix in fibrotic diseases. Here we demonstrate a novel link between transforming growth factor-β and the canonical Wnt pathway. TGF-β stimulates canonical Wnt signalling in a p38-dependent manner by decreasing the expression of the Wnt antagonist Dickkopf-1. Tissue samples from human fibrotic diseases show enhanced expression of Wnt proteins and decreased expression of Dickkopf-1. Activation of the canonical Wnt pathway stimulates fibroblasts in vitro and induces fibrosis in vivo. Transgenic overexpression of Dickkopf-1 ameliorates skin fibrosis induced by constitutively active TGF-β receptor type I signalling and also prevents fibrosis in other TGF-β-dependent animal models. These findings demonstrate that canonical Wnt signalling is necessary for TGF-β-mediated fibrosis and highlight a key role for the interaction of both pathways in the pathogenesis of fibrotic diseases

Optimising treatment in relapsed, refractory multiple myeloma

Novel agents in multiple myeloma (MM), notably the proteasome inhibitors ixazomib and carfilzomib, the therapeutic monoclonal antibodies daratumumab and elotuzumab, and the new immunomodulatory drug pomalidomide, have helped to transform treatment paradigms for relapsed/refractory disease. Research into triplets containing novel agents has supported their superior efficacy over standard doublet combinations for relapsed/refractory MM. Toxicity profile is generally favourable and there is also emerging evidence of quality-of-life benefit. Importantly, novel agents can help address some of the key treatment challenges in myeloma, offering the opportunity for clinicians to more closely align therapeutic choices with individual patient needs. This is particularly important for specific subpopulations where obvious unmet needs still exist, such as in elderly, unfit or frail patients, those with high-risk cytogenetic abnormalities and patients burdened with toxicity-related complications and comorbidities. In this article, we review the available data and evidence for novel agents in the relapsed/refractory setting, and discuss their key role in tailored treatment strategies aimed at optimising current clinical practice. © 2020 Journal of Global Pharma Technology. All rights reserved