Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity.

Multiple myeloma (MM) is a plasma cell disorder that develops in the bone marrow (BM) and is characterized by uncontrolled proliferation and the ability to disseminate to different sites of the skeleton. Sialofucosylated structures, particularly Sialyl Lewis a/x (SLea/x), facilitate the homing of MM cells into the BM, leading to resistance to bortezomib in vivo. Platelets have been shown to play an important role in tumor metastasis. Platelets can bind to the surface of cancer cells, forming a "cloak" that protects them from the shear stress of the bloodstream and natural killer (NK) cell-mediated cytotoxicity. In this study, we showed that the presence of SLea/x induced a strong binding of MM cells to P-selectin, leading to specific and direct interactions with platelets, which could be inhibited by a P-selectin-blocking antibody. Importantly, platelets surrounded SLea/x-enriched MM cells, protecting them from NK cell-mediated cytotoxicity. The interactions between the platelets and MM cells were also detected in BM samples obtained from MM patients. Platelet binding to SLea/x-enriched MM cells was increased in patients with symptomatic disease and at relapse. These data suggest an important role of SLea/x and platelets in MM disease progression and resistance to therapy.

Bispecific Antibodies in Multiple Myeloma: Opportunities to Enhance Efficacy and Improve Safety.

Multiple myeloma (MM) is the second most common haematological neoplasm of adults in the Western world. Overall survival has doubled since the advent of proteosome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. However, patients with adverse cytogenetics or high-risk disease as determined by the Revised International Staging System (R-ISS) continue to have poorer outcomes, and triple-refractory patients have a median survival of less than 1 year. Bispecific antibodies (BsAbs) commonly bind to a tumour epitope along with CD3 on T-cells, leading to T-cell activation and tumour cell killing. These treatments show great promise in MM patients, with the first agent, teclistamab, receiving regulatory approval in 2022. Their potential utility is hampered by the immunosuppressive tumour microenvironment (TME), a hallmark of MM, which may limit efficacy, and by undesirable adverse events, including cytokine release syndrome (CRS) and infections, some of which may be fatal. In this review, we first consider the means of enhancing the efficacy of BsAbs in MM. These include combining BsAbs with other drugs that ameliorate the effect of the immunosuppressive TME, improving target availability, the use of BsAbs directed against multiple target antigens, and the optimal time in the treatment pathway to employ BsAbs. We then discuss methods to improve safety, focusing on reducing infection rates associated with treatment-induced hypogammaglobulinaemia, and decreasing the frequency and severity of CRS. BsAbs offer a highly-active therapeutic option in MM. Improving the efficacy and safety profiles of these agents may enable more patients to benefit from these novel therapies and improve outcomes for patients with high-risk disease.

Challenges in managing patients on anticoagulation: Thrombocytopenia, resumption after bleeding and recurrent thrombosis.

Prescribing of anticoagulation is increasing worldwide. This is partly reflective of an aging population with cardiovascular comorbidities such as arrhythmias and prosthetic heart valves, alongside improvements in cancer treatments and survival. In this review, we discuss three common challenges faced by clinicians. These concern the management of patients with thrombosis and thrombocytopenia, resumption of anticoagulation in patients with a history of gastrointestinal or intracranial haemorrhage, and how to approach and treat a patient with recurrent thrombosis on anticoagulation. We consider the available evidence including relevant published recommendations and propose practical management suggestions to aid clinicians faced with these dilemmas.

Non-factor therapies for bleeding disorders: A primer for the general haematologist.

Management of patients with severe bleeding disorders, particularly haemophilia A and B, and to a lesser extent, von Willebrand disease, has come on leaps and bounds over the past decade. Until recently, patients relied upon the administration of factor concentrates to prevent or treat bleeding episodes. Factor administration requires intravenous access and, in up to one-third of patients, leads to the development of neutralising antibodies, or inhibitors, which are associated with more frequent bleeding episodes and higher morbidity. Novel non-factor therapies may offer a solution to these unmet needs. In this review, we discuss the factor mimetics, particularly emicizumab, and the rebalancing agents, which inhibit antithrombin, tissue factor pathway inhibitor and activated protein C, and novel treatments to enhance von Willebrand factor levels. We review the available trial data, unanswered questions and challenges associated with these new treatment modalities. Finally, we provide practical management algorithms to aid the general haematologist when faced with a patient receiving emicizumab who requires surgery or may develop bleeding.

Practical management of the haemorrhagic complications of myeloproliferative neoplasms.

Myeloproliferative neoplasms can be associated with bleeding manifestations which can cause significant morbidities. Although haematologists are aware of the likelihood of this complication in the setting of myeloproliferative neoplasms, it may often be overlooked especially in patients with no extreme elevation of blood counts and those with myelofibrosis. Acquired von Willebrand syndrome and platelet dysfunction are the two common diagnoses to be considered in this regard. In this review article, we discuss the mechanisms for the development of these rare bleeding disorders, their diagnosis and practical management.

Trends in autologous stem cell transplantation for newly diagnosed multiple myeloma: Changing demographics and outcomes in European Society for Blood and Marrow Transplantation centres from 1995 to 2019.

Multiple myeloma (MM) accounts for 10% of haematological malignancies. Overall survival (OS) has improved in recent years due to increased use of autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed MM and the advent of novel agents, including proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. To assess trends in ASCT including patient selection, choice of induction regimen, depth of response and survival, we performed a retrospective analysis of all patients undergoing first ASCT for MM in European Society for Blood and Marrow Transplantation centres between 1995 and 2019. A total of 117 711 patients across 575 centres were included. The number of transplants performed increased sevenfold across the study period. The median age increased from 55 to 61 years, and the percentage of patients aged >65 years rose from 7% to 30%. Use of chemotherapy-based induction fell significantly, being largely replaced by bortezomib-based regimens. The two-year complete response rate increased from 22% to 42%. The five-year progression-free survival and OS rates increased from 28% to 31% and from 52% to 69%, respectively. Transplant mortality fell from 5.9% to 1.5%. Ongoing advances in MM treatment may challenge the future role of ASCT. However, at the current time, ASCT remains central to the MM treatment paradigm.

Port removal in patients receiving emicizumab prophylaxis: A single centre experience and review of the literature.

INTRODUCTION: Treatment of patients with Haemophilia A has improved significantly in recent years since the advent of novel therapeutic agents such as emicizumab. The low annualised bleeding rates associated with emicizumab have liberated many patients from the need for central venous access devices (CVAD). Optimal peri-operative management of CVAD removal is not currently known and there are no specific formal recommendations available. AIM: We reviewed outcomes in a paediatric cohort in our centre undergoing CVAD removal without pre-operative factor or bypassing agent and reviewed the literature regarding port removal in patients on Emicizumab. METHODS: Ten male patients with severe Haemophilia A underwent CVAD removal without planned administration of factor concentrate or bypassing agent. Patients were monitored in hospital for 24 h with routine laboratory testing pre- and post-operatively. RESULTS: No significant bleeding episodes occurred in any patient, no patient required factor concentrate or bypassing agent and no patients were readmitted due to bleeding within 7 days of surgery. CONCLUSION: We propose that, in the era of emicizumab, prophylactic factor administration pre-operatively for elective CVAD removal is not required in the majority of cases.

The evolving status of immunotherapies in multiple myeloma: the future role of bispecific antibodies.

Treatment outcomes in multiple myeloma (MM) have improved dramatically over the past 10 years. However, patients with high-risk disease such as those with Stage III disease by the Revised International Staging System, the presence of adverse cytogenetics, or who are refractory to proteosome inhibitors, immunomodulatory drugs and monoclonal antibodies may have dismal outcomes. These patients represent an urgent ongoing need in MM. One of the hallmarks of MM is immune dysfunction and a tumour-permissive immune microenvironment. Ameliorating the immune-paresis could lead to improved outcomes. The role of immunotherapies has been growing at an exponential pace with numerous agents under development in clinical trials. In the present review, we provide an overview of immunotherapies in MM, focussing on bispecific antibodies (BsAbs). We review efficacy outcomes from the published clinical trials and consider the important safety aspects of these therapies, in particular the risk of cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome, and how these compare with patients receiving chimeric antigen receptor T cells. We discuss the MM epitopes being targeted by BsAbs, either in clinical or preclinical stages, and we consider where these therapies might best fit within the future ever-changing paradigm of MM treatment.

Lessons Learned From a Case of Behcet's Disease Presenting With Fever and Life-Threatening Venous Thromboembolism.

Infection mimics pose a challenge in the world of infectious diseases. Fever of unknown origin (FUO) requires careful consideration for a broad range of diagnoses. The answer often lies in a careful history and dedicated clinical examination. A delay in diagnosis can result in greater morbidity for the patient. We present the diagnostic challenges in a patient with an infection mimic, Behcet's disease (BD), who presented with recurrent venous thromboembolism (VTE) and fever of unknown origin (FUO). We present the case of a 53-year-old male of Irish Caucasian ethnicity who presented with a history of fevers and recurrent VTE at a university hospital in Dublin, Ireland. Past medical history includes schistosomiasis, which was treated following a trip to sub-Saharan Africa. Our patient was previously diagnosed with a provoked deep vein thrombosis (DVT). He went on to experience four subsequent episodes of VTE, including DVT, pulmonary embolism (PE), and cerebral venous sinus thrombosis (CVST) while on different forms of anticoagulation. On each of these occasions, there was a concern for sepsis due to fevers > 38°C and a C-reactive protein (CRP) > 200 mg/L. The infection workup included routine laboratory tests, blood and urine cultures, CT of the abdomen and pelvis (CTAP), echocardiogram, and PET-CT, all of which were unrevealing. However, a focused clinical examination revealed evidence of subtle scrotal and oral ulceration, pustulation, and erythema at several sites in his upper limb following venesection and cannulation. In this context, a diagnosis of Behcet's disease was considered. A diagnosis of Behcet's disease can only be confidently made after the exclusion of other potential etiologies. In this case, we had to consider a broad range of infectious (malaria, schistosomiasis, rickettsial disease, and endocarditis) and noninfectious (malignancy, antiphospholipid syndrome (APS), myeloproliferative disorders, and paroxysmal nocturnal hemoglobinuria (PNH)) diseases. A delay in diagnosis comes at the cost of increased morbidity and mortality for the patient. A detailed history and clinical examination are key, in addition to a high index of suspicion. Following the induction of high-dose steroid, our patient is doing very well on maintenance adalimumab. From an anticoagulation perspective, he is warfarinized and has not had any further episodes of VTE.

Cyclophosphamide alters the tumor cell secretome to potentiate the anti-myeloma activity of daratumumab through augmentation of macrophage-mediated antibody dependent cellular phagocytosis.

Multiple Myeloma (MM) is a malignant disorder of plasma cells which, despite significant advances in treatment, remains incurable. Daratumumab, the first CD38 directed monoclonal antibody, has shown promising activity alone and in combination with other agents for MM treatment. Daratumumab is thought to have pleiotropic mechanisms of activity including natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). With the knowledge that CD38-expressing NK cells are depleted by daratumumab, we sought to investigate a potential mechanism of enhancing macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) by combining daratumumab with cyclophosphamide (CTX). Cyclophosphamide's immunomodulatory function was investigated by conditioning macrophages with tumor cell secretome collected from cyclophosphamide treated MM cell lines (CTX-TCS). Flow cytometry analysis revealed that CTX-TCS conditioning augmented the migratory capacity of macrophages and increased CD32 and CD64 Fcγ receptor expression on their cell surface. Daratumumab-specific tumor clearance was increased by conditioning macrophages with CTX-TCS in a dose-dependent manner. This effect was impeded by pre-incubating macrophages with Cytochalasin D (CytoD), an inhibitor of actin polymerization, indicating macrophage-mediated ADCP as the mechanism of clearance. CD64 expression on macrophages directly correlated with MM cell clearance and was essential to the observed synergy between cyclophosphamide and daratumumab, as tumor clearance was attenuated in the presence of a FcγRI/CD64 blocking agent. Cyclophosphamide independently enhances daratumumab-mediated killing of MM cells by altering the tumor microenvironment to promote macrophage recruitment, polarization to a pro-inflammatory phenotype, and directing ADCP. These findings support the addition of cyclophosphamide to existing or novel monoclonal antibody-containing MM regimens.

A review of anticoagulation in patients with central nervous system malignancy: between a rock and a hard place.

The incidence and prevalence of patients who develop primary and secondary metastatic central nervous system cancer (CNS) is increasing. This is a consequence of advancements in the sensitivity and availability of diagnostic imaging, and improved therapeutic options, leading to increased detection of CNS malignancies and improved survival. These patients are at very high risk of thrombosis as well as haemorrhage, and the optimum management of anticoagulation can be challenging for treating clinicians, particularly as robust prospective evidence is sparse. In this focused review, we discuss (1) risk factors for thrombosis and bleeding in these patients, (2) management of acute venous thromboembolism (VTE) including evidence for direct oral anticoagulants, and how to approach patients with contraindications to anticoagulation, (3) ambulatory VTE prophylaxis, (4) VTE prophylaxis in patients who have undergone craniotomy for cancer, and (5) management of anticoagulation-related intracranial haemorrhage. Based on review of the available literature and author opinion, we propose practical management algorithms to aid clinicians faced with treating CNS cancer patients with thrombosis or CNS haemorrhage.

Beyond DNA Damage: Exploring the Immunomodulatory Effects of Cyclophosphamide in Multiple Myeloma.

The alkylating agent cyclophosphamide has been used in the treatment of multiple myeloma for over 60 years. At low doses, cyclophosphamide also has significant immunomodulatory activity, which can be used to modify the immunosuppressive tumor microenvironment in order to augment responses to existing therapies. Immune-mediated therapies are becoming more widespread in modern approaches to myeloma treatment. In this review, we discuss the effects cyclophosphamide has on the immune system, and how it can be used synergistically with other treatment modalities including the immunomodulatory agents, monoclonal antibodies and cellular therapies.

The CD38low natural killer cell line KHYG1 transiently expressing CD16F158V in combination with daratumumab targets multiple myeloma cells with minimal effector NK cell fratricide.

Multiple myeloma (MM) is a clonal plasma cell malignancy typically associated with the high and uniform expression of the CD38 transmembrane glycoprotein. Daratumumab is a humanized IgG1κ CD38 monoclonal antibody (MoAb) which has demonstrated impressive single agent activity even in relapsed refractory MM patients as well as strong synergy with other anti-MM drugs. Natural Killer (NK) cells are cytotoxic immune effector cells that mediate in vivo tumour immunosurveillance. NK cells also play an important role during MoAb therapy by inducing antibody dependent cellular cytotoxicity (ADCC) via their FcγRIII (CD16) receptor. Furthermore, 15% of the population express a naturally occurring variant of CD16 harbouring a single-point polymorphism (F158V). However, the contribution of NK cells to the efficacy of daratumumab remains debatable as clinical data clearly indicate the rapid depletion of CD38high peripheral blood NK cells in patients upon daratumumab administration. In contrast, CD38low peripheral blood NK cells have been shown to survive daratumumab mediated fratricide in vivo, while still retaining their potent anti-MM cytolytic effector functions ex vivo. Therefore, we hypothesize that transiently expressing the CD16F158V receptor using a "safe" mRNA electroporation-based approach on CD38low NK cells in combination with daratumumab could represent a novel therapeutic option for treatment of MM. In the present study, we investigate a NK cell line (KHYG-1), derived from a patient with aggressive NK cell leukemia, as a platform for generating CD38low NK cells expressing CD16F158V which can be administered as an "off-the-shelf" therapy to target both CD38high and CD38low tumour clones in patients receiving daratumumab.

Management of bleeding and procedures in patients on antiplatelet therapy.

Antiplatelet medications have long been the mainstay for secondary prevention in cardiovascular disorders. More recently, with the advent of coronary stents, there has been an increased use of more potent antiplatelet agents to prevent stent occlusion. Since these drugs are antithrombotic, it is not unusual for them to be associated with serious bleeding, particularly intracranial and gastrointestinal haemorrhage. There are no robust guidelines on how to manage these clinical situations, although there have been some important studies published recently in this area. Similarly, there is very limited evidence on how to manage urgent surgery in patients receiving these medications. In this review, we provide updated guidance on the management of bleeding and surgery on antiplatelet drugs while stressing the need for further studies to provide evidence-based guidelines.

Current and emerging immunotherapeutic approaches to the treatment of multiple myeloma.

Multiple myeloma (MM) has a worldwide incidence of 1-5/100,000/year. Outcomes have improved significantly in recent years following incorporation of immunomodulatory drugs and proteasome inhibitors into standard-of-care regimes. MM is profoundly immunosuppressive, enabling immune evasion, proliferation and disease progression. The role of the immune system in MM is becoming increasingly characterized and understood, and numerous therapies are under development or in routine clinical use targeting these elements of MM pathogenesis. In this review we discuss the immunosuppressive effects of MM, then the therapies targeting these defects. Specifically, we review the monoclonal and bispecific antibodies, alongside adoptive cellular therapies currently under investigation.

Venous thromboembolism in multiple myeloma - choice of prophylaxis, role of direct oral anticoagulants and special considerations.

Multiple myeloma is associated with a significant risk of venous thromboembolism (VTE), causing substantial levels of morbidity and mortality. The thrombogenicity of myeloma is multifactorial, with disease- and treatment-related factors playing important roles. Immunomodulatory drugs (IMiDs) and high-dose dexamethasone, in particular, are known to enhance the thrombotic potential of myeloma. For this reason, assessment of the VTE risk has long been advocated prior to treatment initiation in patients with myeloma requiring IMiD-based regimens. However, despite routine use of thromboprophylaxis, these patients can still develop VTE and its sequelae. The optimum choice and dose of thromboprophylactic drug is not entirely clear, and with this, there is growing interest regarding use of the direct oral anticoagulants in this setting. In this review we discuss the pathogenesis of thrombosis in multiple myeloma, its relation to some of the commonly used chemotherapeutic regimens, current risk stratification and the evidence supporting the different anticoagulants used as thromboprophylaxis. We propose an amended risk stratification, and consider management of challenging patients, including those with renal impairment and recurrent thrombosis.