Maintenance lenalidomide in newly diagnosed transplant eligible and non-eligible myeloma patients; profiling second primary malignancies in 4358 patients treated in the Myeloma XI Trial

Background: Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan. Methods: Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively. Findings: In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p = 0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p = 0.10). The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p = 0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients. Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n = 25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients. Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed. Interpretation: This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes. Funding: Primary financial support was from Cancer Research UK [ C1298/A10410]

What is the Oxygen Isotope Composition of Venus? The Scientific Case for Sample Return from Earth’s “Sister” Planet

Venus is Earth’s closest planetary neighbour and both bodies are of similar size and mass. As a consequence, Venus is often described as Earth’s sister planet. But the two worlds have followed very different evolutionary paths, with Earth having benign surface conditions, whereas Venus has a surface temperature of 464 °C and a surface pressure of 92 bar. These inhospitable surface conditions may partially explain why there has been such a dearth of space missions to Venus in recent years.The oxygen isotope composition of Venus is currently unknown. However, this single measurement (Δ17O) would have first order implications for our understanding of how large terrestrial planets are built. Recent isotopic studies indicate that the Solar System is bimodal in composition, divided into a carbonaceous chondrite (CC) group and a non-carbonaceous (NC) group. The CC group probably originated in the outer Solar System and the NC group in the inner Solar System. Venus comprises 41% by mass of the inner Solar System compared to 50% for Earth and only 5% for Mars. Models for building large terrestrial planets, such as Earth and Venus, would be significantly improved by a determination of the Δ17O composition of a returned sample from Venus. This measurement would help constrain the extent of early inner Solar System isotopic homogenisation and help to identify whether the feeding zones of the terrestrial planets were narrow or wide.Determining the Δ17O composition of Venus would also have significant implications for our understanding of how the Moon formed. Recent lunar formation models invoke a high energy impact between the proto-Earth and an inner Solar System-derived impactor body, Theia. The close isotopic similarity between the Earth and Moon is explained by these models as being a consequence of high-temperature, post-impact mixing. However, if Earth and Venus proved to be isotopic clones with respect to Δ17O, this would favour the classic, lower energy, giant impact scenario.We review the surface geology of Venus with the aim of identifying potential terrains that could be targeted by a robotic sample return mission. While the potentially ancient tessera terrains would be of great scientific interest, the need to minimise the influence of venusian weathering favours the sampling of young basaltic plains. In terms of a nominal sample mass, 10 g would be sufficient to undertake a full range of geochemical, isotopic and dating studies. However, it is important that additional material is collected as a legacy sample. As a consequence, a returned sample mass of at least 100 g should be recovered.Two scenarios for robotic sample return missions from Venus are presented, based on previous mission proposals. The most cost effective approach involves a “Grab and Go” strategy, either using a lander and separate orbiter, or possibly just a stand-alone lander. Sample return could also be achieved as part of a more ambitious, extended mission to study the venusian atmosphere. In both scenarios it is critical to obtain a surface atmospheric sample to define the extent of atmosphere-lithosphere oxygen isotopic disequilibrium. Surface sampling would be carried out by multiple techniques (drill, scoop, “vacuum-cleaner” device) to ensure success. Surface operations would take no longer than one hour.Analysis of returned samples would provide a firm basis for assessing similarities and differences between the evolution of Venus, Earth, Mars and smaller bodies such as Vesta. The Solar System provides an important case study in how two almost identical bodies, Earth and Venus, could have had such a divergent evolution. Finally, Venus, with its runaway greenhouse atmosphere, may provide data relevant to the understanding of similar less extreme processes on Earth. Venus is Earth’s planetary twin and deserves to be better studied and understood. In a wider context, analysis of returned samples from Venus would provide data relevant to the study of exoplanetary systems

Constraints on the Cosmic Expansion History from GWTC-3

This material is based upon work supported by NSFʼs LIGO Laboratory, which is a major facility fully funded by the National Science Foundation. The authors also gratefully acknowledge the support of the Science and Technology Facilities Council (STFC) of the United Kingdom, the Max-Planck-Society (MPS), and the State of Niedersachsen/Germany for support of the construction of Advanced LIGO and construction and operation of the GEO600 detector. Additional support for Advanced LIGO was provided by the Australian Research Council. The authors gratefully acknowledge the Italian Istituto Nazionale di Fisica Nucleare (INFN), the French Centre National de la Recherche Scientifique (CNRS), and the Netherlands Organization for Scientific Research (NWO), for the construction and operation of the Virgo detector and the creation and support of the EGO consortium. The authors also gratefully acknowledge research support from these agencies as well as by the Council of Scientific and Industrial Research of India, the Department of Science and Technology, India, the Science & Engineering Research Board (SERB), India, the Ministry of Human Resource Development, India, the Spanish Agencia Estatal de Investigación (AEI), the Spanish Ministerio de Ciencia e Innovación and Ministerio de Universidades, the Conselleria de Fons Europeus, Universitat i Cultura and the Direcció General de Política Universitaria i Recerca del Govern de les Illes Balears, the Conselleria d’Innovació Universitats, Ciència i Societat Digital de la Generalitat Valenciana and the CERCA Programme Generalitat de Catalunya, Spain, the National Science Centre of Poland and the European Union–European Regional Development Fund, Foundation for Polish Science (FNP), the Swiss National Science Foundation (SNSF), the Russian Foundation for Basic Research, the Russian Science Foundation, the European Commission, the European Social Funds (ESF), the European Regional Develop- ment Funds (ERDF), the Royal Society, the Scottish Funding Council, the Scottish Universities Physics Alliance, the Hungarian Scientific Research Fund (OTKA), the French Lyon Institute of Origins (LIO), the Belgian Fonds de la Recherche Scientifique (FRS-FNRS), Actions de Recherche Concertées (ARC) and Fonds Wetenschappelijk Onderzoek–Vlaanderen (FWO), Bel- gium, the Paris Île-de-France Region, the National Research, Development and Innovation Office Hungary (NKFIH), the National Research Foundation of Korea, the Natural Science and Engineering Research Council Canada, Canadian Foundation for Innovation (CFI), the Brazilian Ministry of Science, Technology, and Innovations, the International Center for Theoretical Physics South American Institute for Fundamental Research (ICTP- SAIFR), the Research Grants Council of Hong Kong, the National Natural Science Foundation of China (NSFC), the Leverhulme Trust, the Research Corporation, the Ministry of Science and Technology (MOST), Taiwan, the United States Department of Energy, and the Kavli Foundation. The authors gratefully acknowledge the support of the NSF, STFC, INFN, and CNRS for provision of computational resources. This work was supported by MEXT, JSPS Leading-edge Research Infrastructure Program, JSPS Grant-in-Aid for Specially Promoted Research 26000005, JSPS Grant-in-Aid for Scientific Research on Innovative Areas 2905: JP17H06358, JP17H06361, and JP17H06364, JSPS Core-to- Core Program A. Advanced Research Networks, JSPS Grant- in-Aid for Scientific Research (S) 17H06133 and 20H05639, JSPS Grant-in-Aid for Transformative Research Areas (A) 20A203: JP20H05854, the joint research program of the Institute for Cosmic Ray Research, University of Tokyo, National Research Foundation (NRF) and Computing Infra- structure Project of KISTI-GSDC in Korea, Academia Sinica (AS), AS Grid Center (ASGC), and the Ministry of Science and Technology (MoST) in Taiwan under grants including AS- CDA-105-M06, Advanced Technology Center (ATC) of NAOJ, Mechanical Engineering Center of KEK. We would like to thank all of the essential workers who put their health at risk during the COVID-19 pandemic, without whom we would not have been able to complete this work.Peer reviewe

Search for gravitational-wave transients associated with magnetar bursts in advanced LIGO and advanced Virgo data from the third observing run

Gravitational waves are expected to be produced from neutron star oscillations associated with magnetar giant f lares and short bursts. We present the results of a search for short-duration (milliseconds to seconds) and longduration (∼100 s) transient gravitational waves from 13 magnetar short bursts observed during Advanced LIGO, Advanced Virgo, and KAGRA’s third observation run. These 13 bursts come from two magnetars, SGR1935 +2154 and SwiftJ1818.0−1607. We also include three other electromagnetic burst events detected by FermiGBM which were identified as likely coming from one or more magnetars, but they have no association with a known magnetar. No magnetar giant flares were detected during the analysis period. We find no evidence of gravitational waves associated with any of these 16 bursts. We place upper limits on the rms of the integrated incident gravitational-wave strain that reach 3.6 × 10−²³ Hz at 100 Hz for the short-duration search and 1.1 ×10−²² Hz at 450 Hz for the long-duration search. For a ringdown signal at 1590 Hz targeted by the short-duration search the limit is set to 2.3 × 10−²² Hz. Using the estimated distance to each magnetar, we derive upper limits upper limits on the emitted gravitational-wave energy of 1.5 × 1044 erg (1.0 × 1044 erg) for SGR 1935+2154 and 9.4 × 10^43 erg (1.3 × 1044 erg) for Swift J1818.0−1607, for the short-duration (long-duration) search. Assuming isotropic emission of electromagnetic radiation of the burst fluences, we constrain the ratio of gravitational-wave energy to electromagnetic energy for bursts from SGR 1935+2154 with the available fluence information. The lowest of these ratios is 4.5 × 103

A joint Fermi-GBM and Swift-BAT analysis of gravitational-wave candidates from the third gravitational-wave observing run

We present Fermi Gamma-ray Burst Monitor (Fermi-GBM) and Swift Burst Alert Telescope (Swift-BAT) searches for gamma-ray/X-ray counterparts to gravitational-wave (GW) candidate events identified during the third observing run of the Advanced LIGO and Advanced Virgo detectors. Using Fermi-GBM onboard triggers and subthreshold gamma-ray burst (GRB) candidates found in the Fermi-GBM ground analyses, the Targeted Search and the Untargeted Search, we investigate whether there are any coincident GRBs associated with the GWs. We also search the Swift-BAT rate data around the GW times to determine whether a GRB counterpart is present. No counterparts are found. Using both the Fermi-GBM Targeted Search and the Swift-BAT search, we calculate flux upper limits and present joint upper limits on the gamma-ray luminosity of each GW. Given these limits, we constrain theoretical models for the emission of gamma rays from binary black hole mergers

A joint Fermi-GBM and Swift-BAT analysis of gravitational-wave candidates from the third gravitational-wave observing run

We present Fermi Gamma-ray Burst Monitor (Fermi-GBM) and Swift Burst Alert Telescope (Swift-BAT) searches for gamma-ray/X-ray counterparts to gravitational-wave (GW) candidate events identified during the third observing run of the Advanced LIGO and Advanced Virgo detectors. Using Fermi-GBM onboard triggers and subthreshold gamma-ray burst (GRB) candidates found in the Fermi-GBM ground analyses, the Targeted Search and the Untargeted Search, we investigate whether there are any coincident GRBs associated with the GWs. We also search the Swift-BAT rate data around the GW times to determine whether a GRB counterpart is present. No counterparts are found. Using both the Fermi-GBM Targeted Search and the Swift-BAT search, we calculate flux upper limits and present joint upper limits on the gamma-ray luminosity of each GW. Given these limits, we constrain theoretical models for the emission of gamma rays from binary black hole mergers

Open data from the third observing run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

Constraints on the cosmic expansion history from GWTC–3

We use 47 gravitational wave sources from the Third LIGO–Virgo–Kamioka Gravitational Wave Detector Gravitational Wave Transient Catalog (GWTC–3) to estimate the Hubble parameter H(z), including its current value, the Hubble constant H0. Each gravitational wave (GW) signal provides the luminosity distance to the source, and we estimate the corresponding redshift using two methods: the redshifted masses and a galaxy catalog. Using the binary black hole (BBH) redshifted masses, we simultaneously infer the source mass distribution and H(z). The source mass distribution displays a peak around 34 M⊙, followed by a drop-off. Assuming this mass scale does not evolve with the redshift results in a H(z) measurement, yielding ${H}_{0}={68}_{-8}^{+12}\,\mathrm{km}\ \,\ {{\rm{s}}}^{-1}\,{\mathrm{Mpc}}^{-1}$ (68% credible interval) when combined with the H0 measurement from GW170817 and its electromagnetic counterpart. This represents an improvement of 17% with respect to the H0 estimate from GWTC–1. The second method associates each GW event with its probable host galaxy in the catalog GLADE+, statistically marginalizing over the redshifts of each event's potential hosts. Assuming a fixed BBH population, we estimate a value of ${H}_{0}={68}_{-6}^{+8}\,\mathrm{km}\ \,\ {{\rm{s}}}^{-1}\,{\mathrm{Mpc}}^{-1}$ with the galaxy catalog method, an improvement of 42% with respect to our GWTC–1 result and 20% with respect to recent H0 studies using GWTC–2 events. However, we show that this result is strongly impacted by assumptions about the BBH source mass distribution; the only event which is not strongly impacted by such assumptions (and is thus informative about H0) is the well-localized event GW190814