The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be ...significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups.
ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive carfilzomib and dexamethasone (carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m2) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients.
Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47·6 months (95% CI 42·5–not evaluable) in the carfilzomib group versus 40·0 months (32·6–42·3) in the bortezomib group (hazard ratio 0·791 95% CI 0·648–0·964, one-sided p=0·010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 16% of 463 patients in the carfilzomib group vs 46 10% of 456 patients in the bortezomib group), hypertension (67 15% vs 15 3%), pneumonia (42 9% vs 39 9%), thrombocytopenia (41 9% vs 43 9%), fatigue (31 7% vs 35 8%), dyspnoea (29 6% vs ten 2%), decreased lymphocyte count (29 6% vs nine 2%), diarrhoea (18 4% vs 39 9%), and peripheral neuropathy (six 1% vs 28 6%). Treatment-related deaths occurred in five (1%) of 463 patients in the carfilzomib group (pneumonia n=2, interstitial lung disease n=1, septic shock n=1, and unknown n=1) and two (<1%) of 456 patients in the bortezomib group (cardiac arrest n=1 and pneumonia n=1).
Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease.
Onyx Pharmaceuticals Inc, an Amgen Inc subsidiary.
ABSTRACT We have detected in ALMA observations CO emission from the nucleus of the Seyfert galaxy NGC 1068. The low-velocity (up to 70 km s−1 relative to systemic) CO emission resolves into a 12 × 7 ...pc structure, roughly aligned with the nuclear radio source. Higher-velocity emission (up to 400 km s−1) is consistent with a bipolar outflow in a direction nearly perpendicular ( 80°) to the nuclear disk. The position-velocity diagram shows that in addition to the outflow, the velocity field may also contain rotation about the disk axis. These observations provide compelling evidence in support of the disk-wind scenario for the active galactic nucleus obscuring torus.
We used the 1.4 GHz NVSS to study radio sources in two color-selected QSO samples: a volume-limited sample of 1313 QSOs defined by M sub(i) < -23 in the redshift range 0.2 < z < 0.45 and a ...magnitude-limited sample of 2471 QSOs with m sub(r) < or =, slant 18.5 and 1.8 < z < 2.5. About 10% were detected above the 2.4 mJy NVSS catalog limit and are powered primarily by active galactic nuclei (AGNs). The space density of the low-redshift QSOs evolves as rho is proportional to (1 + z)6. In both redshift ranges the flux-density distributions and luminosity functions of QSOs stronger than 2.4 mJy are power laws, with no features to suggest more than one kind of radio source. Extrapolating the power laws to lower luminosities predicts the remaining QSOs should be extremely radio quiet, but they are not. Most were detected statistically on the NVSS images with median peak flux densities S sub(p)(mJy beam super(-1)) approximate 0.3 and 0.05 in the low- and high-redshift samples, corresponding to spectral luminosities logL sub(1.4GHz)(W Hz super(-1)) approximate 22.7 and 24.1, respectively. We suggest that the faint radio sources are powered by star formation at rates M ~ 20 M sub(middot in circle) yr super(-1) in the moderate luminosity (median left angle bracketM sub(i)right angle bracket approximate -23.4) low-redshift QSOs and M ~ 500 M sub(middot in circle) yr super(-1) in the very luminous (left angle bracketM sub(i)right angle bracket approximate -27.5) high-redshift QSOs. Such luminous starbursts left angle bracketlog(L sub(IR)/L sub(middot in circle))right angle bracket ~ 11.2 and 12.6, respectively are consistent with "quasar mode" accretion in which cold gas flows fuel both AGN and starburst.
We have performed a search over 3440 deg2 of Epoch 1 (2017-2019) of the Very Large Array Sky Survey to identify unobscured quasars in the optical (0.2 < z < 3.2) and obscured active galactic nuclei ...(AGNs) in the infrared that have brightened dramatically in the radio over the past one to two decades. These sources would have been previously classified as "radio-quiet" quasars based on upper limits from the Faint Images of the Radio Sky at Twenty cm survey (1993-2011), but they are now consistent with "radio-loud" quasars ( ). A quasi-simultaneous, multiband (∼1-18 GHz) follow-up study of 14 sources with the VLA has revealed compact sources (<0 1 or <1 kpc) with peaked radio spectral shapes. The high-amplitude variability over decadal timescales at 1.5 GHz (100% to >2500%) but roughly steady fluxes over a few months at 3 GHz are inconsistent with extrinsic variability due to propagation effects, thus favoring an intrinsic origin. We conclude that our sources are powerful quasars hosting compact/young jets. This challenges the generally accepted idea that "radio-loudness" is a property of the quasar/AGN population that remains fixed on human timescales. Our study suggests that frequent episodes of short-lived AGN jets that do not necessarily grow to large scales may be common at high redshift. We speculate that intermittent but powerful jets on subgalactic scales could interact with the interstellar medium, possibly driving feedback capable of influencing galaxy evolution.
We present new subarcsecond-resolution Karl G. Jansky Very Large Array (VLA) imaging at 10 GHz of 155 ultraluminous (Lbol ∼ 1011.7-1014.2 L ) and heavily obscured quasars with redshifts z ∼ 0.4-3. ...The sample was selected to have extremely red mid-infrared-optical color ratios based on data from the Wide-Field Infrared Survey Explorer (WISE) along with a detection of bright, unresolved radio emission from the NRAO VLA Sky Survey (NVSS) or Faint Images of the Radio Sky at Twenty cm Survey. Our high-resolution VLA observations have revealed that the majority of the sources in our sample (93 out of 155) are compact on angular scales <0 2 (≤1.7 kpc at z ∼ 2). The radio luminosities, linear extents, and lobe pressures of our sources are similar to young radio active galactic nuclei (e.g., gigahertz-peaked spectrum GPS and compact steep-spectrum CSS sources), but their space density is considerably lower. Application of a simple adiabatic lobe expansion model suggests relatively young dynamical ages (∼104-7 yr), relatively high ambient ISM densities (∼1-104 cm−3), and modest lobe expansion speeds (∼30-10,000 km s−1). Thus, we find our sources to be consistent with a population of newly triggered, young jets caught in a unique evolutionary stage in which they still reside within the dense gas reservoirs of their hosts. Based on their radio luminosity function and dynamical ages, we estimate that only ∼20% of classical large-scale FR I/II radio galaxies could have evolved directly from these objects. We speculate that the WISE-NVSS sources might first become GPS or CSS sources, of which some might ultimately evolve into larger radio galaxies.
Abstract
We present radio spectra spanning 0.1–10 GHz for the sample of heavily obscured luminous quasars with extremely red mid-infrared-optical colors and compact radio emission. The spectra are ...constructed from targeted 10 GHz observations and archival radio survey data that together yield 6–11 flux-density measurements for each object. Our primary result is that most (62%) of the sample have peaked or curved radio spectra and many (37%) could be classified as Gigahertz-Peaked Spectrum (GPS) sources. This indicates compact emission regions likely arising from recently triggered radio jets. Assuming synchrotron self-absorption (SSA) generates the peaks, we infer compact source sizes (3–100 pc) with strong magnetic fields (6–100 mG) and young ages (30–10
4
yr). Conversely, free-free absorption (FFA) could also create peaks due to the high column densities associated with the deeply embedded nature of the sample. However, we find no correlations between the existence or frequency of the peaks and any parameters of the MIR emission. The high-frequency spectral indices are steep (
α
≈ −1) and correlate, weakly, with the ratio of MIR photon energy density to magnetic energy density, suggesting that the spectral steepening could arise from inverse Compton scattering off the intense MIR photon field. This study provides a foundation for combining multifrequency and mixed-resolution radio survey data for understanding the impact of young radio jets on the ISM and star-formation rates of their host galaxies.
faGithub
The phase III RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma (ENDEAVOR) trial showed significantly ...improved progression-free survival and overall survival (OS) with carfilzomib (56 mg/m2) and dexamethasone (Kd56) versus bortezomib and Kd56 (Vd) in patients with relapsed or refractory multiple myeloma (RRMM). We report updated OS and safety data after 6 months of additional follow-up.
Patients with RRMM (1-3 previous lines of therapy) were randomized 1:1 to Kd56 or Vd. Median OS was estimated using the Kaplan–Meier method; OS was compared between treatment groups using Cox proportional hazards models.
As of July 19, 2017, median follow-up was 44.3 months for Kd56 and 43.7 months for Vd. Median OS was 47.8 months (Kd56) versus 38.8 months (Vd; hazard ratio, 0.76; 95% confidence interval, 0.633-0.915). OS was longer with Kd56 versus Vd within age and cytogenetic subgroups, and according to number of previous lines of therapy, previous bortezomib exposure, previous lenalidomide exposure, and lenalidomide-refractory status. Exposure-adjusted incidences per 100 patient-years of adverse events (AEs) were 1352.07 for Kd56 and 1754.86 for Vd; for Grade ≥3 AEs, these values were 162.31 and 175.90.
With median follow-up of approximately 44 months, clinically meaningful improvements in OS were observed with Kd56 versus Vd, including in all subgroups examined. The Kd56 safety profile was consistent with previous analyses.
In this updated analysis of patients with relapsed/refractory multiple myeloma (RRMM) from the RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma (ENDEAVOR) trial, clinically meaningful overall survival improvements continue to be observed with carfilzomib 56 mg/m2 and dexamethasone (Kd56; n = 464) versus bortezomib and dexamethasone (n = 465), including in key patient subgroups. With longer-term data, the favorable benefit-risk profile of Kd56 continues to support its use as a standard-of-care in RRMM.
The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent ...lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of four (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of six prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic adverse events (AE) were common. Three grade 5 AE occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL (clinicaltrials gov. Identifier: NCT01076543).
In ENDEAVOR, carfilzomib (56 mg/m2) and dexamethasone (Kd56) demonstrated longer progression-free survival (PFS) over bortezomib and dexamethasone (Vd) in patients with relapsed/refractory multiple ...myeloma (RRMM). Here we evaluated Kd56 vs Vd by baseline renal function in a post hoc exploratory subgroup analysis. The intent-to-treat population included 929 patients (creatinine clearance CrCL ≥15 to <50 mL/min, n = 85 and n = 99; CrCL 50 to <80 mL/min, n = 186 and n = 177; and CrCL ≥80 mL/min, n = 193 and n = 189 for Kd56 and Vd arms, respectively). In these respective subgroups, median PFS was 14.9 vs 6.5 months (hazard ratio HR, 0.49; 95% confidence interval CI, 0.320-0.757), 18.6 vs 9.4 months (HR, 0.48; 95% CI, 0.351-0.652), and not reached (NR) vs 12.2 months (HR, 0.60; 95% CI, 0.434-0.827) for those receiving Kd56 vs Vd, respectively; median overall survival (OS) was 42.1 vs 23.7 months (HR, 0.66; 95% CI, 0.443-0.989), 42.5 vs 32.8 months (HR, 0.83; 95% CI, 0.626-1.104), and NR vs 42.3 months (HR, 0.75; 95% CI, 0.554-1.009). Complete renal response (ie, CrCL improvement to ≥60 mL/min in any 2 consecutive visits if baseline CrCL <50 mL/min) rates were 15.3% (95% CI, 8.4-24.7) and 14.1% (95% CI, 8.0-22.6) for those receiving Kd56 vs Vd, respectively. In a combined Kd56 and Vd analysis, complete renal responders had longer median PFS (14.1 vs 9.4 months; HR, 0.805; 95% CI, 0.438-1.481) and OS (35.3 vs 29.7 months; HR, 0.91; 95% CI, 0.524-1.577) vs nonresponders. Grade ≥3 adverse event rates in the respective subgroups were 87.1% vs 79.4%, 84.4% vs 71.8%, and 77.1% vs 65.9% for those receiving Kd56 vs Vd, respectively. Thus, Kd56 demonstrated PFS and OS improvements over Vd in RRMM patients regardless of their baseline renal function. The ENDEAVOR trial was registered at www.clinicaltrials.gov as #NCT01568866.
•ENDEAVOR reported clinically meaningful PFS and OS improvements with Kd56 vs Vd in RRMM patients with varying degrees of renal impairment.•Patients with complete renal response had superior PFS and OS outcomes compared with nonresponders across treatment groups.
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