Ixazomib as consolidation and maintenance versus observation in patients with relapsed multiple myeloma eligible for salvage autologous stem-cell transplantation (Myeloma XII [ACCoRD]): interim analysis of a multicentre, open-label, randomised, phase 3 trial

Background The efficacy of consolidation and maintenance in the context of salvage autologous haematopoietic stem-cell transplantation (HSCT) for relapsed multiple myeloma remains unclear. We aimed to assess whether consolidation after salvage autologous HSCT, using ixazomib, thalidomide, and dexamethasone, followed by maintenance with single agent ixazomib is superior to observation. Methods This is an interim analysis of Myeloma XII (ACCorD; referred to as ACCorD hereafter), an open-label, randomised, controlled, phase 3 trial done at 79 hospitals in the UK. Eligible patients were aged 18 years or older, had relapsed multiple myeloma with measurable disease, an ECOG performance status of 2 or less with adequate renal, hepatobiliary, pulmonary, and cardiac function, and required treatment for first progressive disease occurring at least 12 months after first autologous HSCT. In a first randomisation, patients were assigned (1:1) to receive either conventional autologous HSCT with melphalan or augmented autologous HSCT with melphalan and ixazomib. In the second randomisation, reported here, patients were assigned (1:1) to consolidation using ixazomib, thalidomide, and dexamethasone (oral ixazomib 4 mg per day on days 1, 8, and 15, oral thalidomide 100 mg per day on days 1–28, and oral dexamethasone 40 mg per day on days 1, 8, 15 and 22 of 28-day cycles), followed by maintenance with single agent ixazomib (oral ixazomib 4 mg per day on days 1, 8, and 15 of 28-day cycles until disease progression or intolerance), or observation. The primary endpoint was progression-free survival, analysed by intention-to-treat. Safety was analysed per-protocol. This study is registered with ISRCTN, ISRCTN10038996, and EudraCT, 2016-000905-35, and recruitment is complete. Findings Between Dec 12, 2017, and April 21, 2023, 206 patients entered the second randomisation (103 in the consolidation and maintenance group and 103 in the observation group). This prespecified interim analysis (data cutoff April 21, 2023), was done at a median follow-up of 27 months (IQR 13–38). Median progression-free survival was 20 months (95% CI 15–29) in the consolidation and maintenance group and 13 months (11–18) in the observation group (hazard ratio 0·55 [95% CI 0·39–0·78]; p=0·0006). Serious adverse events were reported in 29 (32%) of 92 patients in the consolidation and maintenance group compared with seven (7%) of 103 patients in the observation group. The most common serious adverse events were infections and infestations in both the consolidation and maintenance group and the observation group. The most common grade 3, 4, or 5 adverse events for patients in the consolidation and maintenance group were upper respiratory infection (seven [8%] of 92 patients). No deaths in the consolidation and maintenance group were deemed treatment related. Interpretation ACCorD provides evidence that an orally administered, deliverable, and tolerable post-salvage autologous HSCT treatment regimen can improve the durability of response for transplantation-eligible patients at first relapse. The findings are of relevance to patients who had durable disease control from autologous HSCT in the first line, representing a viable alternative to continuous parentally-administered relapse therapies. Funding Cancer Research UK, Takeda Oncology

Origins of the Ambient Solar Wind: Implications for Space Weather

The Sun's outer atmosphere is heated to temperatures of millions of degrees, and solar plasma flows out into interplanetary space at supersonic speeds. This paper reviews our current understanding of these interrelated problems: coronal heating and the acceleration of the ambient solar wind. We also discuss where the community stands in its ability to forecast how variations in the solar wind (i.e., fast and slow wind streams) impact the Earth. Although the last few decades have seen significant progress in observations and modeling, we still do not have a complete understanding of the relevant physical processes, nor do we have a quantitatively precise census of which coronal structures contribute to specific types of solar wind. Fast streams are known to be connected to the central regions of large coronal holes. Slow streams, however, appear to come from a wide range of sources, including streamers, pseudostreamers, coronal loops, active regions, and coronal hole boundaries. Complicating our understanding even more is the fact that processes such as turbulence, stream-stream interactions, and Coulomb collisions can make it difficult to unambiguously map a parcel measured at 1 AU back down to its coronal source. We also review recent progress -- in theoretical modeling, observational data analysis, and forecasting techniques that sit at the interface between data and theory -- that gives us hope that the above problems are indeed solvable.Comment: Accepted for publication in Space Science Reviews. Special issue connected with a 2016 ISSI workshop on "The Scientific Foundations of Space Weather." 44 pages, 9 figure

Study of Z → llγ decays at √s = 8 TeV with the ATLAS detector

This paper presents a study of Z → llγ decays with the ATLAS detector at the Large Hadron Collider. The analysis uses a proton–proton data sample corresponding to an integrated luminosity of 20.2 fb−1 collected at a centre-ofmass energy √s = 8 TeV. Integrated fiducial cross-sections together with normalised differential fiducial cross-sections, sensitive to the kinematics of final-state QED radiation, are obtained. The results are found to be in agreement with stateof-the-art predictions for final-state QED radiation. First measurements of Z → llγ γ decays are also reported

Search for leptoquark pair production decaying into te−te¯ + or tμ−t¯μ+ in multi-lepton final states in pp collisions at √s = 13 TeV with the ATLAS detector

A search for leptoquark pair production decaying into te−te¯ + or tμ−t¯μ+ in final states with multiple leptons is presented. The search is based on a dataset of pp collisions at √s = 13 TeV recorded with the ATLAS detector during Run 2 of the Large Hadron Collider, corresponding to an integrated luminosity of 139 fb−1. Four signal regions, with the requirement of at least three light leptons (electron or muon) and at least two jets out of which at least one jet is identified as coming from a b-hadron, are considered based on the number of leptons of a given flavour. The main background processes are estimated using dedicated control regions in a simultaneous fit with the signal regions to data. No excess above the Standard Model background prediction is observed and 95% confidence level limits on the production cross section times branching ratio are derived as a function of the leptoquark mass. Under the assumption of exclusive decays into te− (tμ−), the corresponding lower limit on the scalar mixed-generation leptoquark mass mLQd mix is at 1.58 (1.59) TeV and on the vector leptoquark mass mU˜1 at 1.67 (1.67) TeV in the minimal coupling scenario and at 1.95 (1.95) TeV in the Yang–Mills scenario

Constraints on spin-0 dark matter mediators and invisible Higgs decays using ATLAS 13 TeV pp collision data with two top quarks and missing transverse momentum in the final state

This paper presents a statistical combination of searches targeting final states with two top quarks and invisible particles, characterised by the presence of zero, one or two leptons, at least one jet originating from a b-quark and missing transverse momentum. The analyses are searches for phenomena beyond the Standard Model consistent with the direct production of dark matter in pp collisions at the LHC, using 139 fb−1 of data collected with the ATLAS detector at a centre-of-mass energy of 13 TeV. The results are interpreted in terms of simplified dark matter models with a spin-0 scalar or pseudoscalar mediator particle. In addition, the results are interpreted in terms of upper limits on the Higgs boson invisible branching ratio, where the Higgs boson is produced according to the Standard Model in association with a pair of top quarks. For scalar (pseudoscalar) dark matter models, with all couplings set to unity, the statistical combination extends the mass range excluded by the best of the individual channels by 50 (25) GeV, excluding mediator masses up to 370 GeV. In addition, the statistical combination improves the expected coupling exclusion reach by 14% (24%), assuming a scalar (pseudoscalar) mediator mass of 10 GeV. An upper limit on the Higgs boson invisible branching ratio of 0.38 (0.30+0.13−0.09) is observed (expected) at 95% confidence level

Deep generative models for fast photon shower simulation in ATLAS

The need for large-scale production of highly accurate simulated event samples for the extensive physics programme of the ATLAS experiment at the Large Hadron Collider motivates the development of new simulation techniques. Building on the recent success of deep learning algorithms, variational autoencoders and generative adversarial networks are investigated for modelling the response of the central region of the ATLAS electromagnetic calorimeter to photons of various energies. The properties of synthesised showers are compared with showers from a full detector simulation using geant4. Both variational autoencoders and generative adversarial networks are capable of quickly simulating electromagnetic showers with correct total energies and stochasticity, though the modelling of some shower shape distributions requires more refinement. This feasibility study demonstrates the potential of using such algorithms for ATLAS fast calorimeter simulation in the future and shows a possible way to complement current simulation techniques

Search for doubly charged Higgs boson production in multi-lepton final states using 139 fb−1 of proton–proton collisions at s√ = 13 TeV with the ATLAS detector

A search for pair production of doubly charged Higgs bosons (H±± ), each decaying into a pair of prompt, isolated, and highly energetic leptons with the same electric charge, is presented. The search uses a proton–proton collision data sample at a centre-of-mass energy of 13 TeV corresponding to an integrated luminosity of 139 fb−1 recorded by the ATLAS detector during Run 2 of the Large Hadron Collider (LHC). This analysis focuses on same-charge leptonic decays, H±±→ℓ±ℓ′± where ℓ,ℓ′=e,μ,τ, in two-, three-, and four-lepton channels, but only considers final states which include electrons or muons. No evidence of a signal is observed. Corresponding upper limits on the production cross-section of a doubly charged Higgs boson are derived, as a function of its mass m(H±±), at 95% confidence level. Assuming that the branching ratios to each of the possible leptonic final states are equal, B(H±±→e±e±)=B(H±±→e±μ±)=B(H±±→μ±μ±)=B(H±±→e±τ±)=B(H±±→μ±τ±)=B(H±±→τ±τ±)=1/6, the observed (expected) lower limit on the mass of a doubly charged Higgs boson is 1080 GeV (1065 GeV) within the left-right symmetric type-II seesaw model, which is the strongest limit to date produced by the ATLAS Collaboration. Additionally, this paper provides the first direct test of the Zee–Babu neutrino mass model at the LHC, yielding an observed (expected) lower limit of m(H±±) = 900 GeV (880 GeV)

Measurements of the production cross-section for a Z boson in association with b- or c-jets in proton–proton collisions at √s = 13 TeV with the ATLAS detector

This paper presents a measurement of the production cross-section of a Z boson in association with bor c-jets, in proton–proton collisions at √s = 13 TeV with the ATLAS experiment at the Large Hadron Collider using data corresponding to an integrated luminosity of 140 fb−1. Inclusive and differential cross-sections are measured for events containing a Z boson decaying into electrons or muons and produced in association with at least one b-jet, at least one c-jet, or at least two b-jets with transverse momentum pT > 20 GeV and rapidity |y| < 2.5. Predictions from several Monte Carlo generators based on next-to-leading-order matrix elements interfaced with a parton-shower simulation, with different choices of flavour schemes for initial-state partons, are compared with the measured cross-sections. The results are also compared with novel predictions, based on infrared and collinear safe jet flavour dressing algorithms. Selected Z+ ≥ 1 c-jet observables, optimized for sensitivity to intrinsic-charm, are compared with benchmark models with different intrinsic-charm fractions