Cancer associated thrombosis (CAT) is associated with significant morbidity and mortality, highlighting an unmet clinical need to improve understanding of the pathophysiology of CAT. Multiple myeloma (MM) is associated with one of the highest rates of thrombosis despite widespread use of thromboprophylactic agents. The pathophysiology of thrombosis in MM is multifactorial and patients with MM appear to display a hypercoagulable phenotype with potential contributory factors including raised von Willebrand factor (VWF) levels, activated protein C resistance, impaired fibrinolysis, and abnormal thrombin generation. In addition, the toxic effect of anti‐myeloma therapies on the endothelium and contribution to thrombosis has been widely described. Elevated VWF/factor VIII (FVIII) plasma levels have been reported in heterogeneous cohorts of patients with MM and other hematological malignancies. In specific studies, high plasma VWF levels have been shown to associate with VTE risk and reduced overall survival. While the mechanisms underpinning this remain unclear, dysregulation of the VWF and A Disintegrin And Metalloprotease Thrombospondin type 1, motif 13 (ADAMTS‐13) axis is evident in certain solid organ malignancies and correlates with advanced disease and thrombosis. Furthermore, thrombotic microangiopathic conditions arising from deficiencies in ADAMTS‐13 and thus an accumulation of prothrombotic VWF multimers have been reported in patients with MM, particularly in association with specific myeloma therapies. This review will discuss current evidence on the pathophysiological mechanisms underpinning thrombosis in MM and in particular summarize the role of VWF/FVIII in hematological malignancies with a focus on thrombotic risk and emerging evidence for contribution to disease progression.

Extramedullary multiple myeloma (or extramedullary disease, EMD) is an aggressive form of multiple myeloma (MM) that occurs when malignant plasma cells become independent of the bone marrow microenvironment. This may occur alongside MM diagnosis or in later stages of relapse and confers an extremely poor prognosis. In the era of novel agents and anti-myeloma therapies, the incidence of EMD is increasing, making this a more prevalent and challenging cohort of patients. Therefore, understanding the underlying mechanisms of bone marrow escape and EMD driver events is increasingly urgent. The role of genomics in MM has been studied extensively; however, much less is known about the genetic background of EMD. Recently there has been an increased focus on driver events for the establishment of distant EMD sites. Generally, high-risk cytogenetic abnormalities and gene signatures are associated with EMD, alongside mutations in RAS signalling pathways. More recently, changes in epigenetic regulation have also been documented, specifically the hypermethylation of DNA promoter regions. Therefore, the focus of this review is to summarize and discuss what is currently known about the genetic background of EMD in MM.

Multiple myeloma (MM) is associated with an increased risk of venous thrombosis (VTE). In the United Kingdom Medical Research Council (MRC) XI study of patients treated with immunomodulatory therapy, the VTE rate was 11.8% despite 87.7% of the patients being on thromboprophylaxis at the time of thrombosis. In order to effectively prevent VTE events in MM patients, a better understanding of patient and disease risk factors that might predict thrombosis is required. We performed a retrospective cohort analysis of over 300 newly diagnosed MM patients at a tertiary referral centre to determine the VTE rate, predictive factors for VTE, value of the Khorana score for MM VTE events and long-term mortality outcomes. Fifty-four percent of the patients were receiving thromboprophylaxis at the time of the VTE event. The mortality odds ratio was 3.3 (95% CI, 2.4–4.5) in patients who developed VTE in comparison to age-matched controls with MM. A younger age at diagnosis and higher white cell count (WCC) were found to be predictive of VTE events. Our data suggest that standard thromboprophylaxis may not be effective in preventing VTE events in myeloma patients, and alternative strategies, which could include higher-intensity thromboprophylaxis in young patients with a high WCC, are necessary.

Introduction Multiple myeloma is an incurable plasma cell malignancy with a strikingly heterogeneous genomic landscape. Other than IgH translocations and hyperdiploidy, only a few alterations are observed in large enough numbers. Amplification of the long arm of chromosome 1 (1q) is among the most common copy number alterations encountered, with a confirmed adverse effect on survival. Gene expression profiling has identified a minimal common amplified region between 1q21 and 1q23 as a probable target of the amplification event, however the actionable gene dependencies in that region have not been explored. In this study, we employ a large number of in-house and publicly available CRISPR, shRNA and drug screens in an effort to characterize the genetic dependencies of 1q-amplified myeloma and discover drugs that target them. Ultimately, we hope to propose a tailored therapeutic strategy for patients with 1q-amplified multiple myeloma. Methods To assess the genetic dependencies of 1q-amplified myeloma, we performed an shRNA screen in multiple myeloma cell lines, targeting genes in the 1q21-1q23 region. Corresponding C911 hairpins were designed for every target shRNA, and DEMETER2 was used to infer on-target effect. To that same end, we analyzed publicly available dependency data from Project Achilles (Whole-genome CRISPR screen, Avana library, 18Q4 release) and Dependency Map (combined RNAi dataset, accessed on 6/20/2018) and looked for differential dependencies in 1q-amplified multiple myeloma cell lines. Different sets of 1q-amplified and non-amplified cell lines were included in each dataset to avoid cell line-specific effects. Genes that both constituted differential dependencies and were differentially expressed were considered as hits. GSEA was used for pathway analysis. To assess differential sensitivity of 1q-amplified myeloma to drugs, we performed a drug screen utilizing the Broad Institute's Drug Repurposing Library-a library of over 5,000 drugs that have cleared varied stages of clinical testing, and compared normalized viability values between 1q-amplified and non-amplified myeloma cell lines. Utilizing publicly available patient data, we also built a 1q-amplification gene expression signature and used it to query the Connectivity Map (CMap) database. Drugs that were predicted to reverse our signature were then used in a new drug screen of myeloma cell lines. Results Through multiple dependency screens, we identified a total of 206 differential dependencies in 1q-amplified myeloma. Out of those, 46 came up in two screens (double hits), while 4 came up in all three datasets (triple hits). CLK-2, a serine/threonine and tyrosine kinase involved in mRNA splicing and POLR3C, a gene encoding a subunit of RNA-polymerase III, were among the triple hits. MCL-1, UBQLN4, CERS2, JTB, BCL9 and PEX19 were among the double hits. With at least four members affected (UBQLN4, UBE2Q1, UBAP2L and UBE2T), the ubiquitin pathway came up as an important differential dependency, while GSEA identified cell cycle as another pathway of essentiality in 1q-amplified multiple myeloma. Next, we searched for differential drug sensitivities utilizing the Drug Repurposing Library as well as a CMap-guided screen, as described above. We identified as hits several compounds targeting the MDM2 ubiquitin ligase as well as compounds related to cell cycle control, including PARP inhibitors and chemotherapeutic agents like fludarabine, thus validating the dependencies discovered in our datasets. Conclusion We employed a combination of multiple in-house and publicly available CRISPR, shRNA and drug screens, in the largest to date effort to characterize and target the genetic dependencies of 1q-amplified multiple myeloma. Cell cycle and the ubiquitin pathway came up as strong dependencies, while the drugs that target them were indeed shown to preferentially kill 1q-amplified myeloma cell lines. Thus, for the first time, our results suggest that patients with 1q-amplified myeloma might benefit from genetically tailored treatment involving cell cycle and ubiquitin inhibitors or a combination thereof. And inasmuch as 1q amplification is one of myeloma's few frequent alterations, this discovery has the exciting potential to affect change in a large number of patients.

Background: Early evidence of COVID-19–associated coagulopathy disseminated rapidly online during the first months of 2020, followed by clinical debate about how best to manage thrombotic risks in these patients. The rapid online spread of case reports was followed by online interim guidelines, discussions, and worldwide online searches for further information. The impact of global online search trends and online discussion on local approaches to coagulopathy in patients with COVID-19 has not been studied. Objective: The goal of this study was to investigate the relationship between online search trends using Google Trends and the rate of appropriate venous thromboembolism (VTE) prophylaxis and anticoagulation therapy in a cohort of patients with COVID-19 admitted to a tertiary hospital in Ireland. Methods: A retrospective audit of anticoagulation therapy and VTE prophylaxis among patients with COVID-19 who were admitted to a tertiary hospital was conducted between February 29 and May 31, 2020. Worldwide Google search trends of the term “COVID-19” and anticoagulation synonyms during this time period were determined and correlated against one another using a Spearman correlation. A P value of <.05 was considered significant, and analysis was completed using Prism, version 8 (GraphPad). Results: A statistically significant Spearman correlation (P<.001, r=0.71) was found between the two data sets, showing an increase in VTE prophylaxis in patients with COVID-19 with increasing online searches worldwide. This represents a proxy for online searches and discussion, dissemination of information, and Google search trends relating to COVID-19 and clotting risk, in particular, which correlated with an increasing trend of providing thromboprophylaxis and anticoagulation therapy to patients with COVID-19 in our tertiary center. Conclusions: We described a correlation of local change in clinical practice with worldwide online dialogue and digital search trends that influenced individual clinicians, prior to the publication of formal guidelines or a local quality-improvement intervention.