Publications by authors named "Guy Pratt"

127 Publications

MUK OPTIMUM protocol: a screening study to identify high-risk patients with multiple myeloma suitable for novel treatment approaches combined with a phase II study evaluating optimised combination of biological therapy in newly diagnosed high-risk multiple myeloma and plasma cell leukaemia.

BMJ Open 2021 Mar 24;11(3):e046225. Epub 2021 Mar 24.

Centre for Myeloma Research, Institute of Cancer Research, London, UK

Introduction: Multiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients.

Methods And Analysis: The Myeloma UK OPTIMUM trial (MUK) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUK), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUK) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUK primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing.

Ethics And Dissemination: Ethics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal.

Trial Registration Number: ISRCTN16847817, May 2017; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-046225DOI Listing
March 2021

PD-1 is imprinted on cytomegalovirus-specific CD4+ T cells and attenuates Th1 cytokine production whilst maintaining cytotoxicity.

PLoS Pathog 2021 Mar 4;17(3):e1009349. Epub 2021 Mar 4.

Institute of Immunology & Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.

PD-1 is expressed on exhausted T cells in cancer patients but its physiological role remains uncertain. We determined the phenotype, function and transcriptional correlates of PD-1 expression on cytomegalovirus-specific CD4+ T cells during latent infection. PD-1 expression ranged from 10-85% and remained stable over time within individual donors. This 'setpoint' was correlated with viral load at primary infection. PD-1+ CD4+ T cells display strong cytotoxic function but generate low levels of Th1 cytokines which is only partially reversed by PD-1 blockade. TCR clonotypes showed variable sharing between PD-1+ and PD-1- CMV-specific cells indicating that PD-1 status is defined either during T cell priming or subsequent clonal expansion. Physiological PD-1+ CD4+ T cells therefore display a unique 'high cytotoxicity-low cytokine' phenotype and may act to suppress viral reactivation whilst minimizing tissue inflammation. Improved understanding of the physiological role of PD-1 will help to delineate the mechanisms, and potential reversal, of PD-1+ CD4+ T cell exhaustion in patients with malignant disease.
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http://dx.doi.org/10.1371/journal.ppat.1009349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963093PMC
March 2021

Genome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia.

Nat Commun 2021 01 28;12(1):665. Epub 2021 Jan 28.

Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.

Prognostication in patients with chronic lymphocytic leukemia (CLL) is challenging due to heterogeneity in clinical course. We hypothesize that constitutional genetic variation affects disease progression and could aid prognostication. Pooling data from seven studies incorporating 842 cases identifies two genomic locations associated with time from diagnosis to treatment, including 10q26.13 (rs736456, hazard ratio (HR) = 1.78, 95% confidence interval (CI) = 1.47-2.15; P = 2.71 × 10) and 6p (rs3778076, HR = 1.99, 95% CI = 1.55-2.55; P = 5.08 × 10), which are particularly powerful prognostic markers in patients with early stage CLL otherwise characterized by low-risk features. Expression quantitative trait loci analysis identifies putative functional genes implicated in modulating B-cell receptor or innate immune responses, key pathways in CLL pathogenesis. In this work we identify rs736456 and rs3778076 as prognostic in CLL, demonstrating that disease progression is determined by constitutional genetic variation as well as known somatic drivers.
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http://dx.doi.org/10.1038/s41467-020-20822-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843618PMC
January 2021

Janus kinase 2 (JAK2) inhibitors in the treatment of multiple myeloma: modulating the myeloma immune microenvironment.

Br J Haematol 2021 Feb 20;192(3):420-422. Epub 2020 Dec 20.

University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

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http://dx.doi.org/10.1111/bjh.17277DOI Listing
February 2021

Renal outcome in patients with newly diagnosed multiple myeloma: results from the UK NCRI Myeloma XI trial.

Blood Adv 2020 11;4(22):5836-5845

Department of Renal Medicine, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom.

Renal injury is a common complication of multiple myeloma (MM) and is associated with adverse outcome. Despite this, the natural history of renal injury in patients with MM remains uncertain especially in the context of intensive therapy and novel therapies. To address the lack of data, we evaluated the renal function of 2334 patients from the UK National Cancer Research Institute Myeloma XI trial at baseline and at 12 months to assess renal function over time and the factors associated with change. Patients who had severe acute kidney injury or a requirement for dialysis were excluded. At 12 months of the 1450 evaluable patients planned for autologous transplantation; 204 (14%) patients had a decline in estimated glomerular filtration rate (eGFR) ≥25% from baseline, 341 (23.5%) had an improvement and 905 (62%) had no significant change in eGFR. Renal outcome at 12 months for the 884 evaluable patients who were not planned for transplant was similar. Improved renal function was more likely if patients were <70 years old, male, had an average eGFR <60 mL per minute per 1.73 m2 and a higher baseline free light chain level >1000 mg/L, and/or a free light chain response of >90%. It did not correlate with monoclonal-protein response, transplantation, or use of a bortezomib-based regimen. We show that with current therapies the proportion of patients who have a significant decline in renal function in the first 12 months is small. The greatest relative improvement in eGFR is seen in patients with high free light chain at baseline and a high light chain response. This trial was registered at http://www.isrctn.com as #49407852.
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http://dx.doi.org/10.1182/bloodadvances.2020002872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686889PMC
November 2020

Anti-bacterial antibodies in multiple myeloma patients at disease presentation, in response to therapy and in remission: implications for patient management.

Blood Cancer J 2020 11 4;10(11):114. Epub 2020 Nov 4.

Institute of Immunology and Immunotherapy, Clinical Immunology Service, University of Birmingham, Birmingham, UK.

Multiple myeloma (MM) is associated with increased risk of infection, but little is known regarding antibody levels against specific bacteria. We assessed levels of polyclonal immunoglobulin and antibacterial antibodies in patients recruited to the TEAMM trial, a randomised trial of antibiotic prophylaxis at the start of anti-myeloma treatment. Polyclonal IgG, IgA and IgM levels were below the reference range in 71%, 83% and 90% of 838 MM patients at diagnosis. Anti-vaccine targeted tetanus toxoid antibodies were protective in 95% of 193 healthy controls but only 41% of myeloma patients. In healthy controls, protective antibodies against 6/12 pneumococcal serotypes, haemophilus and meningococcus A were present in 67%, 41% and 56% compared to just 15%, 21% and 17% of myeloma patients. By 1 year, myeloma patients IgG levels had recovered for 57% of patients whilst the proportion with protective levels of IgG against thymus-dependent protein antigen tetanus toxoid had changed little. In contrast the proportions of patients with protective levels against thymus independent polysaccharide antigens pneumococcus, haemophilus and meningococcus had fallen from 15 to 7%, 21 to 0% and 17 to 11%. Findings highlight the need for strategies to protect patients against bacterial infections during therapy and vaccination programmes during remission.
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http://dx.doi.org/10.1038/s41408-020-00370-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642409PMC
November 2020

Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial.

Br J Haematol 2021 Mar 15;192(6):997-1005. Epub 2020 Aug 15.

Department of Haematological Medicine, King's College Hospital NHS Trust, London, UK.

Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression.
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http://dx.doi.org/10.1111/bjh.17044DOI Listing
March 2021

Bortezomib, Melphalan, Dexamethasone: A New Standard of Care for AL Amyloidosis?

Authors:
Guy Pratt

J Clin Oncol 2020 10 4;38(28):3243-3244. Epub 2020 Aug 4.

University Hospitals Birmingham, National Health Service Foundation Trust, Birmingham, United Kingdom.

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http://dx.doi.org/10.1200/JCO.20.01904DOI Listing
October 2020

Post-transplant Monoclonal Gammopathy of Renal Significance: A Case Series.

Transplant Proc 2020 Apr 3;52(3):857-864. Epub 2020 Mar 3.

Department of Renal Medicine, University Hospitals Birmingham, Birmingham, United Kingdom.

Monoclonal gammopathy of renal significance (MGRS) is a new concept with evolving evidence for treatment. MGRS in the transplant kidney is a rare cause of renal transplant dysfunction that can lead to graft loss. Most cases of post-transplant MGRS are due to recurrent disease. Clone-specific chemotherapy is required to target the underlying clone, and this may improve graft survival; however, this can be challenging, as most patients are elderly with age-related comorbidities and may have complications associated with increasing immunosuppression. Here, we report 3 cases of renal allograft MGRS, and each case highlights different challenges in the diagnosis and management of this condition.
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http://dx.doi.org/10.1016/j.transproceed.2019.12.040DOI Listing
April 2020

Levofloxacin prophylaxis in patients with myeloma - Authors' reply.

Lancet Oncol 2020 02;21(2):e69

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

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http://dx.doi.org/10.1016/S1470-2045(20)30020-6DOI Listing
February 2020

Low-dose Btk inhibitors selectively block platelet activation by CLEC-2.

Haematologica 2021 01 1;106(1):208-219. Epub 2021 Jan 1.

Institute for Cardiovascular and Metabolic Research, University of Reading, UK.

Inhibitors of the tyrosine kinase Btk have been proposed as novel antiplatelet agents. In this study we show that low concentrations of the Btk inhibitor ibrutinib block CLEC-2-mediated activation and tyrosine phosphorylation including Syk and PLCγ2 in human platelets. Activation is also blocked in patients with X-linked agammaglobulinemia (XLA) caused by a deficiency or absence of Btk. In contrast, the response to GPVI is delayed in the presence of low concentrations of ibrutinib or in patients with XLA, and tyrosine phosphorylation of Syk is preserved. A similar set of results is seen with the second-generation inhibitor, acalabrutinib. The differential effect of Btk inhibition in CLEC-2 relative to GPVI signalling is explained by the positive feedback role involving Btk itself, as well as ADP and thromboxane A2 mediated activation of P2Y12 and TP receptors, respectively. This feedback role is not seen in mouse platelets and, consistent with this, CLEC-2-mediated activation is blocked by high but not by low concentrations of ibrutinib. Nevertheless, thrombosis was absent in 8 out of 13 mice treated with ibrutinib. These results show that Btk inhibitors selectively block activation of human platelets by CLEC-2 relative to GPVI suggesting that they can be used at 'low dose' in patients to target CLEC-2 in thrombo-inflammatory disease.
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http://dx.doi.org/10.3324/haematol.2019.218545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776357PMC
January 2021

Long-Term Ibrutinib Therapy Reverses CD8 T Cell Exhaustion in B Cell Chronic Lymphocytic Leukaemia.

Front Immunol 2019 12;10:2832. Epub 2019 Dec 12.

Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.

Chronic Lymphocytic Leukaemia (CLL) is associated with immune suppression and susceptibility to infection. CD8 T cell numbers are increased and demonstrate elevated expression of PD-1 and impaired function. The mechanisms driving these features of exhaustion are uncertain but are likely to include chronic immune recognition of tumor and/or infectious agents. We investigated the number, phenotype and function of total and virus-specific CD8+ T cells in 65 patients with CLL and 14 patients undergoing long-term ibrutinib therapy (median 21 months). Ibrutinib substantially reduced the number of both CD3+ T cells and CD8+ T cells. Importantly, this was associated with a reduction in PD-1 expression on CD8+ T cells (median 28 vs. 24%; = 0.042) and 3.5 fold increase in cytokine production following mitogen stimulation. The influence of ibrutinib on antigen-specific CD8+ T cell function was assessed by HLA-peptide tetramers and revealed increased IFNγ and TNFα cytokine responses following stimulation with CMV or EBV peptides together with a 55% reduction in the frequency of "inflated" virus-specific CD8+ T cells. These findings reveal that long-term ibrutinib therapy is associated with substantial reversal of T cell exhaustion in B-CLL and is likely to contribute to the reduced infection risk seen in association with this agent.
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http://dx.doi.org/10.3389/fimmu.2019.02832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921985PMC
November 2020

Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL.

Blood 2020 02;135(6):411-428

Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.

Spontaneous regression is a recognized phenomenon in chronic lymphocytic leukemia (CLL) but its biological basis remains unknown. We undertook a detailed investigation of the biological and clinical features of 20 spontaneous CLL regression cases incorporating phenotypic, functional, transcriptomic, and genomic studies at sequential time points. All spontaneously regressed tumors were IGHV-mutated with no restricted IGHV usage or B-cell receptor (BCR) stereotypy. They exhibited shortened telomeres similar to nonregressing CLL, indicating prior proliferation. They also displayed low Ki-67, CD49d, cell-surface immunoglobulin M (IgM) expression and IgM-signaling response but high CXCR4 expression, indicating low proliferative activity associated with poor migration to proliferation centers, with these features becoming increasingly marked during regression. Spontaneously regressed CLL displayed a transcriptome profile characterized by downregulation of metabolic processes as well as MYC and its downstream targets compared with nonregressing CLL. Moreover, spontaneous regression was associated with reversal of T-cell exhaustion features including reduced programmed cell death 1 expression and increased T-cell proliferation. Interestingly, archetypal CLL genomic aberrations including HIST1H1B and TP53 mutations and del(13q14) were found in some spontaneously regressing tumors, but genetic composition remained stable during regression. Conversely, a single case of CLL relapse following spontaneous regression was associated with increased BCR signaling, CLL proliferation, and clonal evolution. These observations indicate that spontaneously regressing CLL appear to undergo a period of proliferation before entering a more quiescent state, and that a complex interaction between genomic alterations and the microenvironment determines disease course. Together, the findings provide novel insight into the biological processes underpinning spontaneous CLL regression, with implications for CLL treatment.
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http://dx.doi.org/10.1182/blood.2019001262DOI Listing
February 2020

Prophylactic levofloxacin to prevent infections in newly diagnosed symptomatic myeloma: the TEAMM RCT.

Health Technol Assess 2019 11;23(62):1-94

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

Background: Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as . There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial.

Objectives: To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients.

Design: Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio.

Setting: A total of 93 NHS hospitals throughout England, Northern Ireland and Wales.

Participants: A total of 977 patients with newly diagnosed symptomatic myeloma.

Intervention: Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year.

Main Outcome Measures: The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond.

Results: In total, 977 patients were randomised (levofloxacin,  = 489; placebo,  = 488). A total of 134 (27%) events (febrile episodes,  = 119; deaths,  = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes,  = 91; deaths,  = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86;  = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; -trend of 0.06). There was no difference in new acquisitions of , methicillin-resistant and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival ( = 0.94).

Limitations: Short duration of prophylactic antibiotics and cost-effectiveness.

Conclusions: During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04).

Trial Registration: Current Controlled Trials ISRCTN51731976.

Funding Details: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta23620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859427PMC
November 2019

Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.

Lancet Oncol 2019 12 23;20(12):1760-1772. Epub 2019 Oct 23.

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

Background: Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma.

Methods: TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35.

Findings: Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8-13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51-0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group.

Interpretation: Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy.

Funding: UK National Institute for Health Research.
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http://dx.doi.org/10.1016/S1470-2045(19)30506-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891230PMC
December 2019

Testing and management for monoclonal gammopathy of uncertain significance and myeloma patients presenting with osteoporosis and fragility fractures.

Rheumatology (Oxford) 2019 07;58(7):1142-1153

Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Multiple myeloma, the second most frequent blood cancer, and its precursor, monoclonal gammopathy of uncertain significance, are associated with an increased risk of fragility fractures. However, current guidelines fail to offer explicit indications for healthcare professionals in terms of testing and thresholds for onward referral. The purpose of this review is to present the association of these conditions and metabolic bone disease and to highlight the importance of considering a diagnosis of monoclonal gammopathy of uncertain significance and myeloma in the context of a secondary fracture prevention assessment and of a multidisciplinary approach in managing these patients.
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http://dx.doi.org/10.1093/rheumatology/kez127DOI Listing
July 2019

Correspondence on: A rare complication of bone marrow aspiration and trephine biopsy: Staphylococcus aureus osteomyelitis and septicaemia - response to Eades & Bapat.

Br J Haematol 2019 07 24;186(2):384. Epub 2019 Apr 24.

Department of Microbiology, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.

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http://dx.doi.org/10.1111/bjh.15930DOI Listing
July 2019

Single arm phase II trial assessing the safety, compliance with and activity of Bezafibrate and medroxyProgesterone acetate (BaP) therapy against myeloid and lymphoid cancers.

Contemp Clin Trials Commun 2019 Jun 10;14:100361. Epub 2019 Apr 10.

Institute of Immunology and Immunotherapy, University of Birmingham, UK.

We previously reported the safety and efficacy of low dose BaP [ezafibrate (Bez) nd Medroxyrogesterone acetate (MPA)] in 20 acute myeloid leukaemia (AML) patients for whom chemotherapy was not an option. This study provided evidence that BaP had anti-AML activity and improved haemopoiesis; absence of haematological toxicity allowed continuous daily administration. Similarly a previous trial in endemic Burkitt lymphoma demonstrated anti-B cell lymphoma activity of low and high dose BaP again in the absence of toxicity. We conducted a study to further evaluate the safety and activity of high dose BaP therapy in adults with AML (and high risk Myelodysplastic Syndromes (MDS)), chronic lymphocytic leukaemia (CLL) or B-cell Non-Hodgkin Lymphoma (BHNL). Eighteen patients were recruited to the study over 20 months, 16 AML/MDS, 1 CLL, and 1 BNHL. Although MPA was well tolerated throughout the study, only 2 patients were able to tolerate Bez treatment for their whole trial duration, indicating that Bez escalation is not feasible in the setting of adult AML/MDS. Thus there has been no obvious benefit in improved haemopoiesis or overt anti-leukaemia activity from the attempts to escalate BaP dose over previous published studies. Since current therapeutic options in MDS are restricted it may be now of value to continue to evaluate low dose BaP based approaches in low risk MDS rather than AML/high risk MDS. Furthermore, screening of low dose BaP against libraries of other already available dugs may identify an addition to BaP that augments the anti-neoplastic efficacy without significant toxicity.
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http://dx.doi.org/10.1016/j.conctc.2019.100361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463739PMC
June 2019

Patient-Reported Outcome Results From the Open-Label, Randomized Phase III Myeloma X Trial Evaluating Salvage Autologous Stem-Cell Transplantation in Relapsed Multiple Myeloma.

J Clin Oncol 2019 07 10;37(19):1617-1628. Epub 2019 Apr 10.

4 University of Leeds, Leeds, United Kingdom.

Purpose: Salvage autologous stem-cell transplantation (sASCT) in patients with multiple myeloma (MM) relapsing after a prior autologous stem-cell transplantation leads to increased remission duration and overall survival. We report a comprehensive study on patient-reported outcomes, including quality of life (QoL) and pain in sASCT.

Methods: Patients were randomly assigned to either sASCT or nontransplantation consolidation (NTC). Pain and QoL were assessed as secondary outcomes using validated QoL instruments (European Organisation for Research and Treatment of Cancer QLQ-C30 and myeloma-specific module, QLQ-MY20; the Brief Pain Inventory [Short Form]; and the Leeds Assessment of Neuropathic Symptoms and Signs [Self-Assessment] scale).

Results: A total of 288 patients (> 96%) consented to the QoL substudy. The median follow-up was 52 months. The European Organisation for Research and Treatment of Cancer QLQ-C30 Global health status scores were higher (better) in the NTC group at 100 days after random assignment ( = .0496), but not at later time points. Pain interference was higher (worse) in the sASCT group than in the NTC group at 6 months after random assignment ( = .0267), with patients with sASCT reporting higher scores for Pain interference with daily living for up to 2 years after random assignment. Patients reporting lower concerns about adverse effects of treatment after sASCT had a time to progression advantage.

Conclusion: Patients with sASCT with relapsed MM demonstrated a comparative reduction in QoL and greater impact of treatment adverse effects lasting for 6 months and up to 2 years for pain, after which patients who had received sASCT reported better outcomes. Patients who experienced lower adverse effects after sASCT had longer time to progression and overall survival, showing the need to improve symptom management peritransplantation. To our knowledge, this study provides the most comprehensive picture of QoL before and after sASCT in patients with relapsed MM.
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http://dx.doi.org/10.1200/JCO.18.01006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858007PMC
July 2019

The impact of cytogenetics on duration of response and overall survival in patients with relapsed multiple myeloma (long-term follow-up results from BSBMT/UKMF Myeloma X Relapse [Intensive]): a randomised, open-label, phase 3 trial.

Br J Haematol 2019 05 6;185(3):450-467. Epub 2019 Feb 6.

Queen's University, Belfast, UK.

The Myeloma X trial (ISCRTN60123120) registered patients with relapsed multiple myeloma. Participants were randomised between salvage autologous stem cell transplantation (ASCT) or weekly cyclophosphamide following re-induction therapy. Cytogenetic analysis performed at trial registration defined t(4;14), t(14;16) and del(17p) as high-risk. The effect of cytogenetics on time to progression (TTP) and overall survival was investigated. At 76 months median follow-up, ASCT improved TTP compared to cyclophosphamide (19 months (95% confidence interval [95% CI] 16-26) vs. 11 months (9-12), hazard ratio [HR]: 0·40, 95% CI: 0·29-0·56, P < 0·001), on which the presence of any single high-risk lesion had a detrimental impact [likelihood ratio test (LRT): P = 0·011]. ASCT also improved OS [67 months (95% CI 59-not reached) vs. 55 months (44-67), HR: 0·64, 95% CI: 0·42-0·99, P = 0·0435], with evidence of a detrimental impact with MYC rearrangement (LRT: P = 0·021). Twenty-one (24·7%) cyclophosphamide patients received an ASCT post-trial, median OS was not reached (95% CI: 39-not reached) for these participants compared to 31 months (22-39), in those who did not receive a post-trial ASCT. The analysis further supports the benefit of salvage ASCT, which may still be beneficial after second relapse in surviving patients. There is evidence that this benefit reduces in cytogenetic high-risk patients, highlighting the need for targeted study in this patient group.
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http://dx.doi.org/10.1111/bjh.15782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519200PMC
May 2019

Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology.

Blood Cancer J 2018 12 21;9(1). Epub 2018 Dec 21.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.
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http://dx.doi.org/10.1038/s41408-018-0162-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315026PMC
December 2018

Fatal systemic angiomatosis with widespread sclerotic skeletal changes, diagnosed with the aid of a bone marrow biopsy: the lymphatics enter the bone marrow.

Pol J Pathol 2018;69(3):314-318

A 56-year-old female presented with popliteal venous thrombosis, splenomegaly, and sclerotic bone lesions. Bone marrow biopsy showed fibrosis, proliferation of abnormal blood vessels and lymphatics, bone remodelling, and no significant changes in haematopoietic elements. Following a relatively indolent initial clinical course, one year later she rapidly deteriorated and died of respiratory failure associated with widespread disease. Ingrowth of podoplanin+ lymphatics mixed with CD34+/podoplanin- blood vessels into the bone marrow is a new finding and may be a unique feature of this disease.
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http://dx.doi.org/10.5114/pjp.2018.79552DOI Listing
May 2019

A rare complication of bone marrow aspiration and trephine biopsy: Staphylococcus aureus osteomyelitis and septicaemia.

Br J Haematol 2019 01 8;184(1). Epub 2018 Nov 8.

University Hospital Birmingham NHS Foundation Trust, Birmingham, UK.

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http://dx.doi.org/10.1111/bjh.15630DOI Listing
January 2019

Successful Renal Outcome in Membranoproliferative Glomerulonephritis Following Treatment of the Underlying Subtle Clone: A Case Report.

Mayo Clin Proc Innov Qual Outcomes 2018 Sep 5;2(3):297-302. Epub 2018 Jun 5.

Department of Renal Medicine, University of Birmingham, Birmingham, UK.

Membranoproliferative glomerulonephritis (MPGN) secondary to a monoclonal gammopathy is a rare glomerular disease and is defined as a monoclonal gammopathy of renal significance. The disease is characterized by glomerular monotypic immunoglobulin deposits and specific changes on light microscopy and electron microscopy. Immunochemistry is required to establish monoclonality, and electron microscopy helps to characterize the deposits ultrastructurally. Investigation for the underlying monoclonal protein should be done. We report a case of MPGN secondary to monoclonal gammopathy of renal significance that responded to treatment of the underlying clone with chemotherapy, resulting in improvement in renal function. Patients with MPGN and immunoglobulin deposition should be evaluated for a monoclonal protein to guide the management strategy.
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http://dx.doi.org/10.1016/j.mayocpiqo.2018.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132210PMC
September 2018