Progression free survival of myeloma patients who become IFE-negative correlates with the detection of residual monoclonal free light chain (FLC) by mass spectrometry.

Deeper responses are associated with improved survival in patients being treated for myeloma. However, the sensitivity of the current blood-based assays is limited. Historical studies suggested that normalisation of the serum free light chain (FLC) ratio in patients who were negative by immunofixation electrophoresis (IFE) was associated with improved outcomes. However, recently this has been called into question. Mass spectrometry (MS)-based FLC assessments may offer a superior methodology for the detection of monoclonal FLC due to greater sensitivity. To test this hypothesis, all available samples from patients who were IFE negative after treatment with carfilzomib and lenalidomide-based induction and autologous stem cell transplantation (ASCT) in the Myeloma XI trial underwent FLC-MS testing. FLC-MS response assessments from post-induction, day+100 post-ASCT and six months post-maintenance randomisation were compared to serum FLC assay results. Almost 40% of patients had discordant results and 28.7% of patients with a normal FLC ratio had residual monoclonal FLC detectable by FLC-MS. FLC-MS positivity was associated with reduced progression-free survival (PFS) but an abnormal FLC ratio was not. This study demonstrates that FLC-MS provides a superior methodology for the detection of residual monoclonal FLC with FLC-MS positivity identifying IFE-negative patients who are at higher risk of early progression.

Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.

Imaging in myeloma: a Royal College of Radiologists national survey of current imaging practice.

AIMS: To evaluate current national imaging practice in myeloma with reference to National Institute for Health and Care Excellence (NICE) guidelines (NG35, 2016) and compare results with an initial survey conducted in 2017 (61 participating sites). MATERIALS AND METHODS: All UK radiology departments treating myeloma patients and with a Royal College of Radiologists (RCR) Audit Lead were invited to participate. Data were collected using an online questionnaire. Descriptive statistics were performed. RESULTS: One hundred and fourteen hospitals supplied data (54% return rate). Skeletal survey (SS) remains the most-commonly performed first-line imaging test for suspected/confirmed myeloma or plasmacytoma (39%, 45/114 hospitals), followed by whole-body magnetic resonance imaging (WBMRI) (27%, 31/114) and whole-body computed tomography (WBCT) (19%, 22/114). Integrated positron-emission tomography/CT (PET/CT) was first-line in 14% (16/114). The NICE recommended initial investigation, WBMRI, is currently offered in 27% of surveyed hospitals (<10% in 2017). Ongoing challenges to implementing WBMRI include scanner availability, financial constraints, reporting time, and radiologist training. CONCLUSION: Despite NICE recommendations regarding WBMRI in diagnosis/follow-up of myeloma, SS (poor sensitivity and specificity) remains the most commonly performed first-line test. Radiologists, haematologists, and patients should continue to emphasise the superiority and benefit of modern and more accurate imaging, such that they are prioritised in clinical service planning.

Effect of beta-blockers on cancer recurrence and survival: a meta-analysis of epidemiological and perioperative studies.

BACKGROUND: The biological perturbation associated with psychological and surgical stress is implicated in cancer recurrence. Preclinical evidence suggests that beta-blockers can be protective against cancer progression. We undertook a meta-analysis of epidemiological and perioperative clinical studies to investigate the association between beta-blocker use and cancer recurrence (CR), disease-free survival (DFS), and overall survival (OS). METHODS: Databases were searched until September 2017, reported hazard ratios (HRs) pooled, and 95% confidence intervals (CIs) calculated. Comparative studies examining the effect of beta-blockers (selective and non-selective) on cancer outcomes were included. The Newcastle Ottawa Scale was used to assess methodological quality and bias. RESULTS: Of the 27 included studies, nine evaluated the incidental use of non-selective beta-blockers, and ten were perioperative studies. Beta-blocker use had no effect on CR. Within subgroups of cancer, melanoma was associated with improved DFS (HR 0.03, 95% CI 0.01-0.17) and OS (HR 0.04, 95% CI 0.00-0.38), while endometrial cancer had an associated reduction in DFS (HR 1.40, 95% CI 1.10-1.80) and OS (HR 1.50, 95% CI 1.12-2.00). There was also reduced OS seen with head and neck and prostate cancer. Non-selective beta-blocker use was associated with improved DFS and OS in ovarian cancer, improved DFS in melanoma, but reduced OS in lung cancer. Perioperative studies showed similar variable effects across cancer types, albeit from a limited data pool. CONCLUSION: Beta-blocker use had no evident effect on CR. The beneficial effect of beta-blockers on DFS and OS in the epidemiological or perioperative setting remains variable, tumour-specific, and of low-level evidence at present.

Analysis of polycyclic aromatic hydrocarbons (PAHs) in air using passive sampling calibrated with active measurements.

There are limited ambient air measurements of extended (beyond EPA Priority 16) lists of polycyclic aromatic hydrocarbons (PAHs). We measured air concentrations of 45 PAHs using passive and active air sampling at 15 sites in a central urban community and one rural site for two years. Passive sampling was conducted with cylindrical XAD-based samplers deployed to capture spatial variability. High volume active samplers with quartz fiber filters for particles and XAD-4 absorbent for gases were deployed at two urban sites and the rural site to calibrate the passive measurements directly. Estimated passive sampling rates (PSRs) were evaluated as functions of meteorological data, seasons, locations, study year, and compared with other studies. Possible particle collection by the passive samplers was evaluated using a variety of particle measurements (TSP, PM10, PM2.5 and ultrafines <100 nm). Total PAHs were statistically associated with ultrafine particle concentrations and to a lesser extent PM2.5 and PM10, but not TSP. PSRs were more variable when PAH mass loadings were lower and near method detection limits; this occurred more often at the rural site. The PSRs were not statistically associated with meteorological conditions in this study, but wind speed had the highest potential to impact PSR results. The resulting passive PAH measurements are reported with respect to proximity to major roadways and other known air emissions types. PSRs were quantifiable for some PAHs that were found predominantly in the particulate phase in active sampling. This information, together with particle fraction calculations from active sampling, were used to estimate the particulate PAH capture of the passive sampler. Summed PAH (∑PAH) passive concentrations were measured within the range of 10-265 ng/m3, with the highest concentrations from naphthalene and the lowest detected concentrations from anthracene. These results indicated a stronger seasonal signal within 200 m of a major roadway.

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma.

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survive and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM-a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26.

Review of the NICE guidelines for multiple myeloma.

In February 2016, the National Institute for Health and Care Excellence (NICE) published guidelines on multiple myeloma. NICE have published numerous guidelines relating to haematology, but this was the first guideline focusing on a single haematological malignancy. The purpose of this review was to highlight the recommendations made in the guideline and the implications for the management of patients in the UK and also internationally. In addition, we review the NICE process and highlight issues around current guideline development.

Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial.

We have carried out the largest randomised trial to date of newly diagnosed myeloma patients, in which lenalidomide has been used as an induction and maintenance treatment option and here report its impact on second primary malignancy (SPM) incidence and pathology. After review, 104 SPMs were confirmed in 96 of 2732 trial patients. The cumulative incidence of SPM was 0.7% (95% confidence interval (CI) 0.4-1.0%), 2.3% (95% CI 1.6-2.7%) and 3.8% (95% CI 2.9-4.6%) at 1, 2 and 3 years, respectively. Patients receiving maintenance lenalidomide had a significantly higher SPM incidence overall (P=0.011). Age is a risk factor with the highest SPM incidence observed in transplant non-eligible patients aged >74 years receiving lenalidomide maintenance. The 3-year cumulative incidence in this group was 17.3% (95% CI 8.2-26.4%), compared with 6.5% (95% CI 0.2-12.9%) in observation only patients (P=0.049). There was a low overall incidence of haematological SPM (0.5%). The higher SPM incidence in patients receiving lenalidomide maintenance therapy, especially in advanced age, warrants ongoing monitoring although the benefit on survival is likely to outweigh risk.

Metabolic plasticity in CLL: adaptation to the hypoxic niche.

Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary chronic lymphoid leukemia (CLL) cells and to interrogate their real-time metabolic responses to hypoxia. Our studies demonstrate considerable metabolic plasticity in CLL cells. Despite being in oxygenated blood, circulating CLL cells are primed for hypoxia as measured by constitutively low level hypoxia-inducible factor (HIF-1α) activity and modest lactate production from glycolysis. Upon entry to hypoxia we observed rapid upregulation of metabolic rates. CLL cells that had adapted to hypoxia returned to the 'primed' state when re-oxygenated and again showed the same adaptive response upon secondary exposure to hypoxia. We also observed HIF-1α independent differential utilization of pyruvate in oxygenated and hypoxic conditions. When oxygenated, CLL cells released pyruvate, but in hypoxia imported pyruvate to protect against hypoxia-associated oxidative stress. Finally, we identified a marked association of slower resting glucose and glutamine consumption, and lower alanine and lactate production with Binet A0 stage samples indicating that CLL may be divided into tumors with higher and lower metabolic states that reflect disease stage.

The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression.

Autoantibodies target the RNA binding protein Ro60 in systemic lupus erythematosus (SLE) and Sjögren's syndrome. However, it is unclear whether Ro60 and its associated RNAs contribute to disease pathogenesis. We catalogued the Ro60-associated RNAs in human cell lines and found that among other RNAs, Ro60 bound an RNA motif derived from endogenous Alu retroelements. Alu transcripts were induced by type I interferon and stimulated proinflammatory cytokine secretion by human peripheral blood cells. Ro60 deletion resulted in enhanced expression of Alu RNAs and interferon-regulated genes. Anti-Ro60-positive SLE immune complexes contained Alu RNAs, and Alu transcripts were up-regulated in SLE whole blood samples relative to controls. These findings establish a link among the lupus autoantigen Ro60, Alu retroelements, and type I interferon.

Primary care management of early stage chronic lymphocytic leukaemia is safe and effective.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the commonest leukaemia in western society. Most patients are detected incidentally at an early stage and require 'watch and wait' follow-up. In the UK, management of Stage A0 CLL varies with some centres advising regular outpatient haematology follow-up, whereas others recommend management within primary care. The safety and effectiveness of these two management options are currently unknown. METHODS: An observational retrospective cohort study in outpatient Haematology clinics at Queen Elizabeth Hospital Birmingham (QEH) and Birmingham Heartlands Hospital (BHH) and primary care practices in West Midlands, UK. All patients diagnosed with stable stage A0 CLL since 2002 at BHH or QEH were identified. At BHH, patients were discharged to primary care follow-up, whilst QEH patients remained under haematology for follow-up. Evidence of disease progression, need for treatment and overall mortality was documented. RESULTS: Two hundred and forty-six Stage A0 CLL patients were identified. One hundred and five (43%) patients were discharged to primary care, whilst 141 (57%) patients were followed up in haematology outpatient clinics. No difference in mortality or need for treatment was found between the two groups. Of those discharged, 93 (66%) remained in primary care. CONCLUSION: The management of stable-stage A0 CLL within primary or secondary care leads to equivalent clinical outcomes. The prevalence of early-stage CLL is expected to increase with the ageing population and management within primary care should be considered as a potentially effective approach.

United Kingdom Myeloma Forum position statement on the use of consolidation and maintenance treatment in myeloma.

Therapeutic advances and the availability of novel agents have significantly improved outcomes in myeloma; yet, it remains incurable and strategies to improve survival continue to be sought. One approach is to prolong the duration of response and increase progression-free survival (PFS) through consolidation or maintenance treatment with regimens that have low toxicity profiles, and do not negatively impact on quality of life. Data from several studies with thalidomide, lenalidomide and bortezomib consistently show improvements in response and PFS, although results have still to be confirmed with respect to overall survival (OS). Despite the promising data, the optimal use of consolidation and maintenance treatment in terms of regimen, dose and duration has yet to be defined. Given the evidence to date, the UK Myeloma Forum believes that both maintenance and consolidation therapy should be considered as treatment options for patients with myeloma. Patients should be encouraged to enrol in clinical studies. This document reviews the current position of maintenance and consolidation for patients with myeloma treated in the UK.

United Kingdom Myeloma Forum (UKMF) position statement on the use of bendamustine in myeloma.

Bendamustine is a unique bifunctional alkylating agent with promising activity in myeloma. Despite the increasing number of studies demonstrating its efficacy in both the upfront and relapse settings, including patients with renal insufficiency, the optimal use of bendamustine, in terms of dosage, schedule and combination with other agents, has yet to be defined. It is currently licensed for use as frontline treatment with prednisolone for patients with myeloma who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib. Studies in relapsed/refractory patients are currently ongoing with other combinations. Given the increasing data to date, the UK Myeloma Forum believes that bendamustine with steroids alone or in combination with a novel agent could be considered for patients with multiply relapsed myeloma. This document provides guidance for the use of bendamustine for patients with myeloma until the results of definitive studies are available.

The relationship between high-sensitivity CRP and polyclonal free light chains as markers of inflammation in chronic disease.

INTRODUCTION: Serum concentrations of polyclonal free light chains (FLC) represent the activity of the adaptive immune system. This study assessed the relationship between polyclonal FLC and the established marker of innate immunity, C-reactive protein (CRP), in chronic and acute disease. METHODS: We utilized four cross-sectional chronic disease patient cohorts: chronic kidney disease (CKD), diabetes, vasculitis and kidney transplantation; and a longitudinal intensive care case series to assess the kinetics of production in acute disease. RESULTS: There was a weak association between polyclonal FLC and high-sensitivity CRP (hs-CRP) in the study cohorts. A longitudinal assessment in acute disease showed a gradual increase in FLC concentrations over time, often when CRP levels were falling, demonstrating clear differences in the response kinetics of CRP and FLC in this setting. CONCLUSION: Polyclonal FLC and hs-CRP provide independent information as to inflammatory status. Prospective studies are now required to assess the utility of hs-CRP and polyclonal FLC in combination for risk stratification in disease populations.

Monoclonal gammopathy of undetermined significance: an update for nephrologists.

Screening for a monoclonal protein is a common part of the assessment of patients presenting with a renal injury. While in the settings of acute kidney injury, chronic kidney disease and proteinuria monoclonal proteins can be associated with significant pathologies such as cast nephropathy, amyloidosis, and light chain deposition disease, they can also be an unrelated finding. The purpose of this review is to provide the nephrologist with an update to the diagnostic assessment and risk stratification of monoclonal proteins to avoid unnecessary investigation and monitoring of those patients with low-risk monoclonal gammopathies.