This paper describes the use of Storm at Twitter. Storm is a realtime fault-tolerant and distributed stream data processing system. Storm is currently being used to run various critical computations in Twitter at scale, and in real-time. This paper describes the architecture of Storm and its methods for distributed scale-out and fault-tolerance. This paper also describes how queries (aka. topologies) are executed in Storm, and presents some operational stories based on running Storm at Twitter. We also present results from an empirical evaluation demonstrating the resilience of Storm in dealing with machine failures. Storm is under active development at Twitter and we also present some potential directions for future work.

Background Maintenance therapy following autologous stem cell transplantation can delay disease progression and prolong survival in multiple myeloma (MM). Ixazomib is ideally suited for maintenance therapy given its efficacy, convenient once-weekly oral dosing, and low toxicity profile. Methods The phase 3, double-blind, placebo-controlled, TOURMALINE-MM3 study randomised 656 patients with newly diagnosed MM from 227 clinical/hospital sites in 30 countries in Europe, the Middle East, Africa,

Real-world assessment of the clinical impact of symptomatic infection with severe acute respiratory syndrome coronavirus (COVID-19 disease) in patients with multiple myeloma receiving systemic anti-cancer therapy Dear Editor, Infection with the novel coronavirus SARS-CoV-2, resulting in an acute respiratory disease (COVID-19), is the cause of the current pneumonia pandemic, with a rapid rise in cases being reported in the European Union and UK. 1,2 The UK index case was identified on January 31, 2020 and, given the rapid spread and high mortality rate of COVID-19, it is imperative to define the impact on patients with co-existing medical conditions. 3 Multiple myeloma (MM), the second-most common haematological malignancy, is a cancer of the mature B-cell lineage, and is associated with both cellular and humoral immune dysfunction that renders patients susceptible to infections, especially of the respiratory tract. [4][5][6][7] This, coupled with a median age at presentation of 70 years in a population with frequent co-existing medical conditions, means the outcomes of MM patients infected with COVID-19 warrants particular attention. We conducted a fully-anonymised prospective clinical audit where only MM patients with documented symptomatic COVID-19, whether managed in the inpatient or outpatient setting, were reported. All patients were tested within the secondary care setting and were receiving systemic anti-cancer therapy (SACT).At the time of analysis (May 18, 2020), 75 completed proformas from MM patients who tested swab-positive for COVID-19 had been received (Table I). The median age of COVID-19-positive MM patients was 73 years (range, 47-88), with 27Á5% of patients >80 years of age. Where ethnicity details were available (n = 51), most (82%) were Caucasian, with 16% being Afro-Caribbean. 41% of patients were newly-diagnosed MM receiving frontline therapy (NDMM); 24% had relapsed from their frontline therapy and were now receiving second-line therapy (1 st REL); and 35% had relapsed and/or refractory disease (RRMM). The median absolute lymphocyte count at presentation with COVID-19 symptoms was 600 cells/ll (range, 0-2500), with 90% of patients demonstrating hypo-gammaglobulinaemia affecting at least 1 sub-class (IgG> IgM>IgA). The male/female ratio was 1Á5, but varied with age (<75 years ratio 2Á33 vs. >75 years ratio 0Á94) as a consequence of significant age difference between the groups (P = 0Á049).The median time from the UK Index case to COVID-19 symptoms was 54 days (range, 23-88). 20Á5% of patients did not have a temperature on presentation but did have a cough, and 16% reported GI symptoms, with 20Á5% of patients acquiring COVID-19 whilst an inpatient for other reasons. 75% had evidence of pulmonary infiltrates primarily detected by chest radiograph. All but three patients were admitted for clinical care. Systemic anticancer therapy (SACT) was stopped a median of 0Á5 days (range, 5-23) after the onset of COVID-19 symptoms. Only nine of 70 patients received critical care support, with five pati...

Emergence of drug resistance to all available therapies is the major challenge to improving survival in myeloma. Cereblon (CRBN) is the essential binding protein of the widely-used IMiD and novel CelMOD drugs in myeloma, as well as certain PROTACs in development for a range of diseases. Using whole genome sequencing data from 455 patients and RNASeq data from 655 patients, including a newly-diagnosed cohort (n=198 WGS, n=437 RNASeq), a lenalidomide (LEN)-refractory cohort (n=203 WGS, n=176 RNASeq) and a pomalidomide (POM)-refractory cohort (n=54 WGS, n=42 RNASeq), we find incremental increase in the frequency of three CRBN aberrations, namely point mutations, copy loss/structural variation and a specific variant transcript (exon 10-spliced), with progressive IMiD exposure, until almost one third of patients have CBRN alterations by the time they are POM-refractory. We find all 3 CRBN aberrations are associated with an inferior outcome to POM in those already refractory to LEN, including those with gene copy loss and structural variation, which has not previously been described. This is the first comprehensive analysis of CBRN alterations in myeloma patients as they progress through therapy, and the largest dataset. It will help inform patient selection for sequential therapies with CRBN-targeting drugs.

Recent years have witnessed a rapid growth in our understanding of the pathogenic property of monoclonal proteins. It is evident that some of these small monoclonal proteins are capable of inducing end-organ damage as a result of their intrinsic physicochemical properties. Hence, an umbrella term, monoclonal gammopathy of clinical significance (MGCS), has been coined to include myriad conditions attributed to these pathogenic proteins. Because kidneys are the most commonly affected organ (but skin, peripheral nerves, and heart can also be involved), we discuss MGRS exclusively in this review. Mechanisms of renal damage may involve direct or indirect effects. Renal biopsy is mandatory and demonstration of monoclonal immunoglobulin in kidney, along with the corresponding immunoglobulin in serum or urine, is key to establish the diagnosis. Pitfalls exist at each diagnostic step, and a high degree of clinical suspicion is required to diagnose MGRS. Recognition of MGRS by hematologists and nephrologists is important, because timely clone-directed therapy improves renal outcomes. Autologous stem cell transplant may benefit selected patients.

Treatment options in multiple myeloma (MM) are increasing with the introduction of complex multi-novel-agent-based regimens investigated in randomized clinical trials. However, application in the real-world setting, including feasibility of and adherence to these regimens, may be limited due to varying patient-, treatment-, and disease-related factors. Furthermore, approximately 40% of real-world MM patients do not meet the criteria for phase 3 studies on which approvals are based, resulting in a lack of representative phase 3 data for these patients. Therefore, treatment decisions must be tailored based on additional considerations beyond clinical trial efficacy and safety, such as treatment feasibility (including frequency of clinic/hospital attendance), tolerability, effects on quality of life (QoL), and impact of comorbidities. There are multiple factors of importance to real-world MM patients, including disease symptoms, treatment burden and toxicities, ability to participate in daily activities, financial burden, access to treatment and treatment centers, and convenience of treatment. All of these factors are drivers of QoL and treatment satisfaction/compliance. Importantly, given the heterogeneity of MM, individual patients may have different perspectives regarding the most relevant considerations and goals of their treatment. Patient perspectives/goals may also change as they move through their treatment course. Thus, the ‘efficacy’ of treatment means different things to different patients, and treatment decision-making in the context of personalized medicine must be guided by an individual’s composite definition of what constitutes the best treatment choice. This review summarizes the various factors of importance and practical issues that must be considered when determining real-world treatment choices. It assesses the current instruments, methodologies, and recent initiatives for analyzing the MM patient experience. Finally, it suggests options for enhancing data collection on patients and treatments to provide a more holistic definition of the effectiveness of a regimen in the real-world setting.

The evolving paradigm of continuous therapy and maintenance treatment approaches in multiple myeloma (MM) offers prolonged disease control and improved outcomes compared to traditional fixed-duration approaches. Potential benefits of long-term strategies include sustained control of disease symptoms, as well as continued cytoreduction and clonal control, leading to unmeasurable residual disease and the possibility of transforming MM into a chronic or functionally curable condition. "Continuous therapy" commonly refers to administering a doublet or triplet regimen until disease progression, whereas maintenance approaches typically involve single-agent or doublet treatment following more intensive prior therapy with autologous stem cell transplant (ASCT) or doublet, triplet, or even quadruplet induction therapy. However, the requirements for agents and regimens within these contexts are similar: treatments must be tolerable for a prolonged period of time, should not be associated with cumulative or chronic toxicity, should not adversely affect patients' quality of life, should ideally be convenient with a minimal treatment burden for patients, and should not impact the feasibility or efficacy of subsequent treatment at relapse. Multiple agents have been and are being investigated as long-term options in the treatment of newly diagnosed MM (NDMM), including the immunomodulatory drugs lenalidomide and thalidomide, the proteasome inhibitors bortezomib, carfilzomib, and ixazomib, and the monoclonal antibodies daratumumab, elotuzumab, and isatuximab. Here we review the latest results with long-term therapy approaches in three different settings in NDMM: (1) maintenance treatment post ASCT; (2) continuous frontline therapy in nontransplant patients; (3) maintenance treatment post-frontline therapy in the nontransplant setting. We also discuss evidence from key phase 3 trials. Our review demonstrates how the paradigm of long-term treatment is increasingly well-established across NDMM treatment settings, potentially resulting in further improvements in patient outcomes, and highlights key clinical issues that will need to be addressed in order to provide optimal benefit.

SummaryThe response of the tumour microenvironment to anti-cancer drugs can influence treatment efficacy. Current drug-screening methodologies fail to distinguish and quantify simultaneously the concomitant effect of drugs on the tumour stroma and cancer cells. To overcome this limitation we have developed a fluorescence-based experimental model that employs mCherrylabelled stromal cells (e.g. bone marrow fibroblastic stromal cells) cocultured in direct contact with enhanced green fluorescent protein-labelled tumour cell lines for accurate assessment of proliferation and viability in both cell compartments and adhesion of tumour cells. Additionally, we used fluorescence-based image analysis to determine morphological changes that correlate with cell function (e.g. morphology of the actin cytoskeleton and nuclearity of osteoclasts to predict their bone resorption activity). Using this platform we have revealed that dexamethasone induces HS5 fibroblast proliferation and contact with multiple myeloma cells via a process involving Src/ c-Abl kinases. Osteoclasts also inhibited dexamethasone-induced apoptosis in myeloma cells while retaining their normal morphology and functionality in bone resorption. Myeloma resistance to dexamethasone mediated by HS5 cells and osteoclasts was reversed by treatment with the Src/c-Abl inhibitor dasatinib but not with bortezomib. This new experimental platform provides a more precise screening of new therapeutics for improved efficacy of tumour cell killing within the bone marrow microenvironment.