Inflammatory profile of lower risk myelodysplastic syndromes.

The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patients with lower risk MDS in comparison to healthy controls and patients with defined autoinflammatory disorders (AIDs). The ASC/NLRP3 specks were significantly elevated in MDS patients compared to healthy controls (p < 0.001) and these levels were comparable to those found in patients with AIDs. The distribution of protein specks positive only for ASC was different to ASC/NLRP3 ones suggesting that other ASC-containing inflammasome complexes might be important in the pathogenesis of MDS. Patients with MDS-SLD had the lowest levels of interleukin (IL)-1ß, tumour necrosis factor (TNF), IL-23, IL-33, interferon (IFN) γ and IFN-α2, compared to other diagnostic categories. We also found that inflammatory cytokine TNF was positively associated with MDS progression to a more aggressive form of disease and IL-6 and IL-1ß with time to first red blood cell transfusion. Our study shows that there is value in analysing inflammatory biomarkers in MDS, but their diagnostic and prognostic utility is yet to be fully validated.

Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper.

Multiple myeloma is a bone marrow-based plasma cell tumour that develops from asymptomatic pre-cursor conditions smouldering myeloma and monoclonal gammopathy of uncertain significance and all are characterised by the presence of a monoclonal protein in the blood. Diagnosis and distinction between these conditions is based on blood tests, the bone marrow biopsy and cross sectional imaging. There are various risk stratification models that group patients with smouldering myeloma into risk groups based on risk of progression to symptomatic disease. Management is mainly observational for patients with smouldering myeloma although clinical trials for high-risk disease may be available. Restaging is required if evidence for progression.

Benefits of switching from intravenous to subcutaneous daratumumab: Perspectives from UK healthcare providers.

Daratumumab is a CD38-directed monoclonal antibody indicated to treat multiple myeloma (MM). Daratumumab was initially administered intravenously (IV), subsequently a subcutaneous (SC) formulation was developed to increase convenience of administration. The UK was an early adopter of SC daratumumab and, as such, this report provides consensus recommendations from a group of UK MM experts, with the aim of facilitating the transition from IV to SC daratumumab for other European healthcare providers. The switch from IV to SC daratumumab has been beneficial to patients and healthcare providers, as it simplifies treatment, reduces pressure on hospitals and can improve patients' quality of life.

Key findings from the UKCCMP cohort of 877 patients with haematological malignancy and COVID-19: disease control as an important factor relative to recent chemotherapy or anti-CD20 therapy.

Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1-2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96-1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09-5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08-2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments.

Unplanned admissions for patients with myeloma in the UK: Low frequency but high costs.

BACKGROUND: Multiple myeloma (MM) is associated with high healthcare resource utilisation and increasing hospitalisation rates. The aim of this study was to characterise the hospital use by patients with MM in the English National Health Service (NHS). METHODS: Routinely-collected aggregate data about all NHS-funded hospital admissions of patients with MM were analysed. Data were obtained from the English Hospital Episodes Statistics on admissions between 1 April 2014 and 31 March 2018. RESULTS: A total of 754,345 admissions were reported over four years, equivalent to a mean of 188,586 admissions per year. Of the 41,845 patients admitted during this period, 42% were women and 58% men. From the total admissions, 90% were elective and 10% unplanned. Mean annual estimated costs over the period were £46 million for elective and £56 million for unplanned admissions. The number of elective admissions increased by 4.5% with costs increasing 1.5% per year; for unplanned admissions, these figures were 4.1% and 9.0%, respectively. CONCLUSIONS: MM is associated with a significant number of hospital admissions and NHS costs. The majority of the hospital admissions are elective, but the highest burden in terms of costs relates to unplanned admissions, with numbers increasing over time.

Navigating the treatment landscape in multiple myeloma: which combinations to use and when?

Multiple myeloma is one of the most common hematological malignancies, affecting mainly elderly patients. The treatment landscape for the management of this disease has evolved significantly over the past 15 years, and a vast array of therapeutics is now available, including immunomodulatory drugs, proteasome inhibitors, histone deacetylase inhibitors, and monoclonal antibodies. As a result, deciding which drugs to use and when, and whether these should be used in a particular order or combination, can be challenging. Although combination regimens are often associated with deeper responses and better long-term outcomes than monotherapy, and are becoming the standard of care, they may result in significant incremental toxicity; hence, a sequential approach may be more appropriate for some patients. In particular, treatment choices can vary depending on whether the patient has newly diagnosed multiple myeloma, is eligible for transplant, has relapsed and/or refractory multiple myeloma, or is considered to have high-risk disease. In this review, we discuss factors to be taken into account when making treatment decisions in each of these settings. We also briefly discuss possible therapeutic strategies involving agents that may become available in the future.

Chart review across EU5 in MM post-ASCT patients.

AIM: To understand the current treatment patterns, clinical outcomes and healthcare resource utilization-associated costs for multiple myeloma patients, post autologous stem cell transplant (ASCT) across Europe. PATIENTS & METHODS: Medical records were used to abstract data for 337 multiple myeloma patients who had received ASCT. RESULTS: Following ASCT, 7% received maintenance therapy prior to progression. Lenalidomide was the most frequently prescribed maintenance, second- and third-line therapy. Monthly resource use was considerably lower in patients who received maintenance therapy (€638.14 vs €1001.74). Median time to progression was longer for patients who had received maintenance therapy. CONCLUSION: The study highlights the diversity in current treatment patterns post-ASCT. Results suggest patients who receive maintenance therapy have a prolonged remission period, and as a result their associated healthcare resource utilization is spread across the treatment pathway.

Healthcare resource utilisation associated with skeletal-related events in European patients with multiple myeloma: Results from a prospective, multinational, observational study.

OBJECTIVES: Patients with multiple myeloma (MM) often experience debilitating skeletal-related events (SREs: pathologic fracture, radiation to bone [RB], surgery to bone [SB] or spinal cord compression [SCC]). This is the first comprehensive, prospective, observational analysis of healthcare resource utilisation (HRU), independently attributed to SREs by investigators, in patients with MM. METHODS: Eligible patients had lytic bone lesions, life expectancy ≥6 months, Eastern Cooperative Oncology Group performance status ≤2 and ≥1 SRE in the 97 days before enrolment. Data were collected retrospectively for 97 days before enrolment and prospectively for 18-21 months. RESULTS: Altogether, 153 patients were enrolled from Germany, Italy, Spain and the United Kingdom. Of the 281 observed SREs, 36.7% required inpatient stays (mean duration: 20.6 days per SRE [standard deviation (SD): 22.9]). SB and SCC were the SREs most likely to require stays (72.3% and 50.0% of SREs, respectively); SCC required the longest mean (SD) stay per event (40.5 [40.8] days). Overall, 179 SREs required outpatient visits; this was most likely for RB (74.8%) and least likely for non-vertebral fracture (50.0%). CONCLUSIONS: All SREs were associated with substantial HRU; therefore, preventing SREs in MM will reduce the economic and resource burden on healthcare systems.

Stem Cell Harvesting after Bortezomib-Based Reinduction for Myeloma Relapsing after Autologous Transplantation: Results from the British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X (Intensive) Trial.

The phase III British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X trial (MMX) demonstrated prospectively, for the first time, superiority of salvage autologous stem cell transplantation over chemotherapy maintenance for multiple myeloma (MM) in first relapse after previous ASCT. However, many patients have stored insufficient stem cells (PBSC) for second ASCT and robust evidence for remobilization after first ASCT is lacking. We report the feasibility, safety, and efficacy of remobilization after bortezomib-doxorubicin-dexamethasone reinduction in MMX and outcomes of second ASCT with these cells. One hundred ten patients underwent ≥1 remobilization with 32 and 4, undergoing second and third attempts, respectively. Toxicities of remobilization were similar to those seen in first-line mobilization. After all attempts, 52% of those with insufficient previously stored PBSC had harvested a sufficient quantity to proceed to second ASCT. Median PBSC doses infused, neutrophil engraftment, and time to discharge after second ASCT were similar regardless of stem cell source, as were the toxicities of second ASCT. No significant differences between PBSC sources were noted in depth of response to ASCT or time to progression. Harvesting after bortezomib-doxorubicin-dexamethasone reinduction for MM at first relapse is safe and feasible and yields a reliable cell product for second ASCT. The study is registered with ClinicalTrials.gov (NCT00747877) and EudraCT (2006-005890-24).

A molecular diagnostic approach able to detect the recurrent genetic prognostic factors typical of presenting myeloma.

Risk stratification in myeloma requires an accurate assessment of the presence of a range of molecular abnormalities including the differing IGH translocations and the recurrent copy number abnormalities that can impact clinical behavior. Currently, interphase fluorescence in situ hybridization is used to detect these abnormalities. High failure rates, slow turnaround, cost, and labor intensiveness make it difficult and expensive to use in routine clinical practice. Multiplex ligation-dependent probe amplification (MLPA), a molecular approach based on a multiplex polymerase chain reaction method, offers an alternative for the assessment of copy number changes present in the myeloma genome. Here, we provide evidence showing that MLPA is a powerful tool for the efficient detection of copy number abnormalities and when combined with expression assays, MLPA can detect all of the prognostically relevant molecular events which characterize presenting myeloma. This approach opens the way for a molecular diagnostic strategy that is efficient, high throughput, and cost effective.

Health resource utilisation associated with skeletal-related events in European patients with lung cancer: Α subgroup analysis from a prospective multinational study.

Bone complications or skeletal-related events (SREs), typically defined as radiation to bone, pathological fractures, surgery to bone and spinal cord compression, occur frequently in patients with bone metastases. As the survival of patients with advanced lung cancer improves, preventing SREs is becoming increasingly clinically relevant. The aim of this analysis was to assess the impact of SREs on health resource utilisation (HRU) in European lung cancer patients with bone metastasis. This multinational, observational study included patients who had at least one SRE in the 97 days prior to enrolment, a life expectancy of ≥6 months and an Eastern Cooperative Oncology Group performance status of 0-2. Data on HRU were retrospectively collected for up to 97 days prior to enrolment with a planned prospective follow-up for up to 18-21 months. The HRU measures included the number and length of inpatient hospitalisations and the number of outpatient visits and procedures. The investigators determined whether each HRU was attributable to a SRE. In total, 135 patients with lung cancer, enrolled at centres in Germany, Italy, Spain and the United Kingdom, contributed 214 SREs to this analysis. The median length [quartile (Q)1, Q3] of follow-up ranged from 1.5 (0.7, 3.3) to 5.6 (2.0, 8.2) months across the countries. Overall, 41% of the SREs required an inpatient stay, with a median (Q1, Q3) duration of 19.0 (6.0, 28.0) days. Spinal cord compression and surgery to bone were the SRE types most frequently requiring inpatient stays. Radiation to bone was associated with the largest number of outpatient visits and procedures. All the SREs resulting from bone metastases in patients with lung cancer contribute considerably to HRU and efforts to minimise the incidence of bone complications in these patients through appropriate treatments may help reduce this burden.

Health resource utilization associated with skeletal-related events in patients with advanced breast cancer: results from a prospective, multinational observational study.

Patients with breast cancer and bone metastases often experience skeletal complications (skeletal-related events [SREs]: pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Prospective data on the health resource burden of SREs are needed for planning healthcare requirements and estimating the value of new treatments, but limited data are available. This prospective, observational study collected health resource utilization (HRU) data independently attributed to SREs by investigators. Eligible patients had bone metastases secondary to breast cancer, life expectancy ≥6 months, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and at least one SRE in the 97 days before enrollment. Data, collected retrospectively for 97 days before enrollment and prospectively for 18-21 months, included number and duration of inpatient stays, outpatient visits, emergency room visits and procedures. Altogether, 223 patients were enrolled from Germany, Italy, Spain and the UK. Of the 457 SREs, 118 (25.8%) were associated with inpatient stays. The mean duration of stay was 19.5 (standard deviation [SD] 19.2) days per SRE (based on 117 SREs). Surgery to bone and spinal cord compression were the SREs most likely to require inpatient stays (77.8% and 57.9% of SREs, respectively), while radiation to bone was the least likely (9.7%). Spinal cord compression required the longest inpatient stay per event (34.2 [SD 30.2] days) and radiation to bone the shortest (14.3 [SD 10.2] days). Overall, 342 SREs (74.8%) required an outpatient visit, with radiation to bone the most likely (85.7%), and surgery to bone the least likely (42.6%). Radiation to bone was also associated with the greatest number of outpatient visits per event (6.8 [SD 6.7] visits). All SREs were associated with substantial HRU therefore, preventing SREs in patients with breast cancer may reduce the burden imposed on healthcare systems.

Health Resource Utilization Associated with Skeletal-Related Events in Patients with Advanced Prostate Cancer: A European Subgroup Analysis from an Observational, Multinational Study.

This study aimed to increase the understanding of health resource utilization (HRU) associated with skeletal-related events (SREs) occurring in patients with bone metastases secondary to advanced prostate cancer. A total of 120 patients from Germany, Italy, Spain and the United Kingdom were enrolled in this observational study. They had bone metastases secondary to prostate cancer and had experienced at least one SRE in the 97 days before giving informed consent. HRU data were collected retrospectively for 97 days before enrolment and prospectively for up to 18-21 months. HRU, including the number and duration of inpatient hospitalizations, number of outpatient and emergency department visits and procedures, was independently attributed by investigators to an SRE. Of the 222 SREs included in this analysis, 26% were associated with inpatient stays and the mean duration per SRE was 21.4 days (standard deviation (SD) 17.8 days). Overall, 174 SREs (78%) required an outpatient visit and the mean number of visits per SRE was 4.6 (SD 4.6). All SREs are associated with substantial HRU. Preventing SREs in patients with advanced prostate cancer and bone metastases may help to reduce the burden to both patients and European healthcare systems.

A gene expression-based predictor for myeloma patients at high risk of developing bone disease on bisphosphonate treatment.

PURPOSE: Myeloma bone disease impairs quality of life and is associated with impaired survival. Even with effective bisphosphonate treatment, a significant proportion of patients still develop skeletal-related events (SRE). Identifying such patients at presentation would allow treatment modification. EXPERIMENTAL DESIGN: To investigate the molecular basis of bone disease at presentation and to develop a predictive signature for patients at high risk of developing SREs on bisphosphonates, 261 presenting myeloma samples were analyzed by global gene expression profiling. The derived "SRE gene signature" was complemented by the integration of associated clinical parameters to generate an optimal predictor. RESULTS: Fifty genes were significantly associated with presenting bone disease, including the WNT signaling antagonist DKK1 and genes involved in growth factor signaling and apoptosis. Higher serum calcium level and the presence of bone disease and hyperdiploidy at presentation were associated with high risk of SRE development. A gene signature derived from the fourteen genes overexpressed in the SRE group was able to identify patients at high risk of developing an SRE on treatment. These genes either belonged to the IFN-induced family or were involved in cell signaling and mitosis. Multivariate logistic model selection yielded an optimal SRE predictor comprising seven genes and calcium level, which was validated as an effective predictor in a further set of patients. CONCLUSIONS: The simple expression-based SRE predictor can effectively identify individuals at high risk of developing bone disease while being on bisphosphonates. This predictor could assist with developing future trials on novel therapies aimed at reducing myeloma bone disease.

Guidelines for supportive care in multiple myeloma 2011.

Supportive care plays an increasingly important role in the modern management of multiple myeloma. While modern treatments have significantly prolonged overall and progression free survival through improved disease control, the vast majority of patients remain incurable, and live with the burden of the disease itself and the cumulative side effects of treatments. Maintenance of quality of life presents challenges at all stages of the disease from diagnosis through the multiple phases of active treatment to the end of life. Written on behalf of the British Committee for Standards in Haematology (BCSH) and the UK Myeloma Forum (UKMF), these evidence based guidelines summarize the current national consensus for supportive and symptomatic care in multiple myeloma in the following areas; pain management, peripheral neuropathy, skeletal complications, infection, anaemia, haemostasis and thrombosis, sedation, fatigue, nausea, vomiting, anorexia, constipation, diarrhoea, mucositis, bisphosphonate-induced osteonecrosis of the jaw, complementary therapies, holistic needs assessment and end of life care. Although most aspects of supportive care can be supervised by haematology teams primarily responsible for patients with multiple myeloma, multidisciplinary collaboration involving specialists in palliative medicine, pain management, radiotherapy and surgical specialities is essential, and guidance is provided for appropriate interdisciplinary referral. These guidelines should be read in conjunction with the BCSH/UKMF Guidelines for the Diagnosis and Management of Multiple Myeloma 2011.