Adoptive immunotherapy and high-risk myeloma

Despite significant improvements in the treatment of multiple myeloma (MM), it remains mostly incurable, highlighting a need for new therapeutic approaches. Patients with high-risk disease characteristics have a particularly poor prognosis and limited response to current frontline therapies. The recent development of immunotherapeutic strategies, particularly T cell-based agents have changed the treatment landscape for patients with relapsed and refractory disease. Adoptive cellular therapies include chimeric antigen receptor (CAR) T cells, which have emerged as a highly promising therapy, particularly for patients with refractory disease. Other adoptive cellular approaches currently in trials include T cell receptor-based therapy (TCR), and the expansion of CAR technology to natural killer (NK) cells. In this review we explore the emerging therapeutic field of adoptive cellular therapy for MM, with a particular focus on the clinical impact of these therapies for patients with high-risk myeloma. </p

Genetic abnormalities in extramedullary multiple myeloma

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. </p

Optimising an innovative xenograft model for inoculation of myeloma cell lines

Introduction: Multiple myeloma (MM) is a haematological condition characterised by abnormal proliferation of plasma cells in the bone marrow. The disease progresses from an asymptomatic phase to MM. Testing drugs preclinically is crucial for developing novel therapies, and the chick embryo xenograft chorioallantoic membrane (CAM) model is gaining popularity compared to other models. Methods: Gelatin was used as a matrix for delivering MM cell lines onto the CAM to mimic tumour growth and facilitate drug testing. Gelatin concentrations of 10%, 8%, and 6% were prepared, and the RPMI 8226 cell line was chosen for experiments. Fertilised hen eggs were prepared for incubation, and on embryonic development day 7 (EDD7), RPMI 8226 MM cells mixed with gelatin were implanted on the CAM. On EDD14, the CAM was excised for histological analysis. Results: In vitro viability analysis demonstrated that 6% and 8% gelatin concentrations were most favourable for cell retention. On EDD14, angiogenic responses and tumour growth were observed. Histological analysis confirmed the presence of plasma cell growth on the CAM. The 8% gelatin concentration had the highest number of vessels, indicating angiogenesis, and also showed good viability. Conclusion: The CAM model combined with gelatin as a delivery matrix shows promise for studying MM and testing novel therapies. Future studies may explore other extracellular matrix components.</p

The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies

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

Hypersialylation and multiple myeloma

There is growing recognition of the importance of sialylation as a critical post translational modification in cancer. In this article we review the role of increased cell surface sialylation (hypersialylation) in Multiple Myeloma as it relates to cellular trafficking and immune evasion. Knowledge of the specific effects of sialic acid on cell trafficking machinery and modulation of immune cell interactions will identify opportunities for therapeutic interventions. The available evidence indicates that hypersialylation facilitates disease progression and negatively impacts on response to treatment and overall survival. Further research is required to fully elucidate the mechanisms through which hypersialylation influences disease biology and therapy resistance with the ultimate goal of developing new treatment approaches to improve the outcomes of patients with Multiple Myeloma

Hypersialylation and multiple myeloma

There is growing recognition of the importance of sialylation as a critical post translational modification in cancer. In this article we review the role of increased cell surface sialylation (hypersialylation) in Multiple Myeloma as it relates to cellular trafficking and immune evasion. Knowledge of the specific effects of sialic acid on cell trafficking machinery and modulation of immune cell interactions will identify opportunities for therapeutic interventions. The available evidence indicates that hypersialylation facilitates disease progression and negatively impacts on response to treatment and overall survival. Further research is required to fully elucidate the mechanisms through which hypersialylation influences disease biology and therapy resistance with the ultimate goal of developing new treatment approaches to improve the outcomes of patients with Multiple Myeloma

Bortezomib-induced hyponatremia: tolvaptan therapy permits continuation of lenalidomide, bortezomib and dexamethasone therapy in relapsed myeloma

The development of hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH) is well recognised in multiple myeloma (MM). SIADH, due to either MM or Bortezomib can be hazardous as severe hyponatremia may develop if large volumes of hypotonic intravenous fluid are used as an adjunct to chemotherapy. We report a case of Bortezomib-induced SIADH, in whom the use of tolvaptan, a vasopressin receptor-2 antagonist, permitted the continuation of triple combination anti-MM therapy with lenalidomide, Bortezomib and dexamethasone (RVD) in a female with aggressive disease, without the development of hyponatremia. Our patient had a rapid relapse, in which the use of Bortezomib as part of an RVD regimen was life-saving. The use of tolvaptan allowed continuation of therapy that is usually halted in other similarly reported cases. This case highlights the possible use of vaptans, which allows an aquaresis to occur by blocking the antidiuretic effects of vasopressin, as a treatment for Bortezomib-induced hyponatremia. </p

Validation of risk-adapted venous thromboembolism prediction in multiple myeloma patients

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 im-munomodulatory therapy, the VTE rate was 11.8% despite 87.7% of the patients being on thrombo-prophylaxis 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

Benign gynaecological pathology causing vascular presentations: three cases of women with peripheral thromboses

Introduction  Benign or malignant gynaecological disease can compress iliac vessels leading to deep vein thrombosis (DVT) or acute arterial ischemia. Women have a higher incidence of thrombosis in comparison to males, with a higher prevalence of pro-thrombotic factors such as pregnancy, use of combined oral contraceptives, and gynaecological pathologies.  Cases  Case 1 is a 45-year old Caucasian woman who presented with a left sided DVT, menorrhagia and anaemia secondary to a multi-fibroid uterus. Case 2 was a 38 year old Caucasian female who presented with a left sided DVT secondary to a singular large uterine fibroid (21cm diameter). Case 3 was a Caucasian female who presented with acute arterial ischemia and contralateral DVT due to compressive effect from a exceptionally large benign ovarian pathology.  Results  This case series highlights the need to consider vascular complications in young female patients as sequelae of possible pelvic pathology.  Conclusion  Investigation for pelvic gynaecological disease should be considered in assessment of women with lower limb thrombotic vascular pathology, especially in the absence of typical vascular risk factors </p

Benign gynaecological pathology causing vascular presentations: three cases of women with peripheral thromboses

Introduction  Benign or malignant gynaecological disease can compress iliac vessels leading to deep vein thrombosis (DVT) or acute arterial ischemia. Women have a higher incidence of thrombosis in comparison to males, with a higher prevalence of pro-thrombotic factors such as pregnancy, use of combined oral contraceptives, and gynaecological pathologies.  Cases  Case 1 is a 45-year old Caucasian woman who presented with a left sided DVT, menorrhagia and anaemia secondary to a multi-fibroid uterus. Case 2 was a 38 year old Caucasian female who presented with a left sided DVT secondary to a singular large uterine fibroid (21cm diameter). Case 3 was a Caucasian female who presented with acute arterial ischemia and contralateral DVT due to compressive effect from a exceptionally large benign ovarian pathology.  Results  This case series highlights the need to consider vascular complications in young female patients as sequelae of possible pelvic pathology.  Conclusion  Investigation for pelvic gynaecological disease should be considered in assessment of women with lower limb thrombotic vascular pathology, especially in the absence of typical vascular risk factors </p