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

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

Elevated von Willebrand factor levels in multiple myeloma: dysregulated mechanisms of both secretion and clearance

We read with great interest the recent publication by Ghansah et al whose work demonstrating increased thrombin generation and differential sensitivity to activated protein C (APC) in samples from patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is an important addition to our growing understanding of the critical factors behind the high rate of thrombosis in MM.1 In particular, we noted that these authors also found raised von Willebrand Factor (VWF) antigen and Factor VIII (FVIII) levels in patients with newly diagnosed MM and, to a lesser extent in patients with MGUS. However, they concluded that the biological mechanisms underpinning raised VWF:Ag levels in MM and MGUS remain unresolved with the authors suggesting endothelial damage may be a key contributing factor. In fact, following on from the work of Ghansah et al, here, we show for the first time that not only is VWF synthesis increased in MM but that VWF circulatory clearance is also reduced in this disease. Furthermore, we also report the novel finding of raised VWF propeptide in precursor MM disease, incorporating both MGUS and smouldering MM (SM), which strengthens the evidence of a hypercoagulable profile in these premalignant conditions.</div

Elevated von Willebrand factor levels in multiple myeloma: dysregulated mechanisms of both secretion and clearance

We read with great interest the recent publication by Ghansah et al whose work demonstrating increased thrombin generation and differential sensitivity to activated protein C (APC) in samples from patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) is an important addition to our growing understanding of the critical factors behind the high rate of thrombosis in MM.1 In particular, we noted that these authors also found raised von Willebrand Factor (VWF) antigen and Factor VIII (FVIII) levels in patients with newly diagnosed MM and, to a lesser extent in patients with MGUS. However, they concluded that the biological mechanisms underpinning raised VWF:Ag levels in MM and MGUS remain unresolved with the authors suggesting endothelial damage may be a key contributing factor. In fact, following on from the work of Ghansah et al, here, we show for the first time that not only is VWF synthesis increased in MM but that VWF circulatory clearance is also reduced in this disease. Furthermore, we also report the novel finding of raised VWF propeptide in precursor MM disease, incorporating both MGUS and smouldering MM (SM), which strengthens the evidence of a hypercoagulable profile in these premalignant conditions.</div