BackgroundThe addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months’ trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority.ObjectivesTo establish whether or not 6 months’ adjuvant trastuzumab is non-inferior to 12 months’ in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival.DesignThis was a Phase III randomised controlled non-inferiority trial.SettingThe setting was 152 NHS hospitals.ParticipantsA total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part.InterventionRandomisation (1 : 1) to 6 months’ or 12 months’ trastuzumab treatment.Main outcomesThe primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months’ trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months’ trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model.ResultsBetween 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months’ trastuzumab and 2043 were randomised to 6 months’ trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years’ median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiorityp = 0.01), demonstrating non-inferiority of 6 months’ trastuzumab. Congruent results were found for overall survival (non-inferiorityp = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiorityp = 0.03 (disease-free-survival) andp = 0.006 (overall survival)]. Six months’ trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients;p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients;p < 0.0001]. Health economic analysis showed that 6 months’ trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months’ trastuzumab, and thus there is a high probability that 6 months’ trastuzumab is cost-effective compared with 12 months’ trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently.LimitationsThe type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered.ConclusionsPERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months’ adjuvant trastuzumab is non-inferior to 12 months’. Six months’ treatment resulted in significantly less cardiac toxicity and fewer severe adverse events.Future workOngoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.Trial registrationCurrent Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

Background: Multiple myeloma is a cancer of plasma cells that is associated with severe immunodeficiency and increased numbers of bacterial infections. The Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial assessed the use of prophylactic levofloxacin in newly diagnosed multiple myeloma patients. Interactions between multiple myeloma disease activity, immunity and infection are central to the TEAMM trial. Active multiple myeloma suppresses immunity and infections delay administration of anti-multiple myeloma therapy. Furthermore, infection-derived inflammation nurtures multiple myeloma activity and resistance to anti-multiple myeloma therapy. Objectives: The aim of this study was to measure biomarkers of (1) immune competence to develop risk stratification of patients for infection to personalise the decision to prescribe antibiotics, (2) myeloma activity to sensitively measure speed and depth of myeloma response and (3) inflammation to identify patients who may be at risk of poor treatment responses. Method: Serum samples were collected from 977 TEAMM trial patients (aged 35–90 years) at randomisation, then every 4 weeks for 16 weeks and again at 1 year. Biomarker levels were compared with samples from healthy controls. Multiplex Luminex® assays (R&D Systems, Minneapolis, MN, USA) and enzyme-linked immunosorbent assays were used for the analysis of biomarkers and anti-viral antibodies were measured by a haemagglutination assay. Results: At baseline, levels of both polyclonal immunoglobulins and anti-bacterial antibodies were below the normal range in most TEAMM trial patients. This immunoparesis was much more severe for antibodies against specific bacterial targets than for total immunoglobulin levels. Levels of anti-bacterial antibodies were below the threshold of protection for 18 of the 19 bacterial antigens tested. More patients aged < 65 years were protected against meningococcal serotypes, Haemophilus influenza type b and tetanus, whereas more patients aged ≥ 65 years were protected against pneumococcal serotypes but there was good protection in only 6% of the TEAMM trial patients. Higher levels of polyclonal immunoglobulins, but not specific anti-bacterial antibodies, were found to be associated with a lower risk of infection and a longer survival. At presentation, levels of neutrophil elastase, calprotectin and interleukin 10 were elevated in TEAMM trial patients, compared with healthy controls. Interleukin 10 levels were related to infection during the trial: patients with interleukin 10 levels ≥ 10 pg/ml had a greater risk of infection than patients with interleukin 10 levels < 10 pg/ml. Levels of soluble CD138 were elevated in 72% of TEAMM trial patients and were decreased in response to therapy, with a complete response seen in 40% of TEAMM trial patients by 16 weeks. Of the 76 TEAMM trial patients achieving a free light chain complete response at 16 weeks, only 30% had a soluble CD138 complete response. Overall, responses in the levels of soluble CD138 did not correlate with free light chain and myeloma monoclonal protein (also known as m-protein) responses, consistent with the fact that soluble CD138 responses reflect a separate aspect of disease activity and clonal size. Levels of procalcitonin were elevated in only 50% of patients who had febrile episodes during the TEAMM trial. Although levels of interleukins 6 and 8 at presentation were lower than in a heathy cohort of patients, lower levels of interleukin 6 were identified at baseline in poor responders than in good responders, and in patients who had febrile and non-febrile infections during the trial than in patients who had only non-febrile episodes. Conclusion: Information from this Efficacy and Mechanism Evaluation project can help inform risk stratification and patient identification strategies to be responsive to individual patient needs. Monitoring levels of free light chains and soluble CD138 can help identify non-responders early and monitoring interleukin 10 levels can help stratify patients for risk of infection. Furthermore, immunisation in remission should be tested. Limitations: The TEAMM trial administered prophylactic antibiotics or placebo for 12 weeks from a new diagnosis of myeloma. Patients were monitored for infections for 16 weeks post diagnosis, with a final set of clinical data gathered at 1 year. Infection data and efficacy of prophylactic antibiotics are available for only the first 16 weeks and survival for the first 52 weeks. This limits long-term data, particularly for progression-free and overall survival. Future work: The TEAMM 2 trial (in preparation) will explore the benefit of prophylactic antibiotics up to 12 months following diagnosis and will explore infection risk post therapy and during remission. Furthermore, some of the key findings will be applied to investigate biomarkers in samples from other UK myeloma trials in which long-term outcome data are available. Trial registration: Current Controlled Trials ISRCTN51731976. Funding: This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership, and will be published in full in Efficacy and Mechanism Evaluation; Vol. 7, No. 10. See the NIHR Journals Library website for further project information.

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.

Helena M Earl, Louise Hiller, Anne-Laure Vallier, Shrushma Loi, Karen McAdam, Luke Hughes-Davies, Adrian N Harnett, Mei-Lin Ah-See, Richard Simcock, Daniel Rea, Sanjay Raj, Pamela Woodings, Mark Harries, Donna Howe, Kerry Raynes, Helen B Higgins, Maggie Wilcox, Chris Plummer, Janine Mansi, Ioannis Gounaris, Betania Mahler–Araujo, Elena Provenzano, Anita Chhabra, Jean E Abraham, Carlos Caldas, Peter S Hall, Christopher McCabe, Claire Hulme, David Miles, Andrew M Wardley, David A Cameron, Janet A Dunn on behalf of PERSEPHONE Steering Committee and Trial Investigators*

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 Clostridium difficile. 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, n = 489; placebo, n = 488). A total of 134 (27%) events (febrile episodes, n = 119; deaths, n = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n = 91; deaths, n = 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; p = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p-trend of 0.06). There was no difference in new acquisitions of C. difficile, methicillin-resistant Staphylococcus aureus 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 (p = 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 Health Technology Assessment; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.

Background: Myeloma causes profound immunodeficiency and recurrent, serious infections. There are approximately 5,500 new UK cases of myeloma per annum; a quarter will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection and early death but this may be associated with healthcare-associated infections (HCAI). Methods: The TEAMM trial was a multicentre randomised, double-blind, placebo-controlled trial in newly-diagnosed myeloma patients randomised to receive Levofloxacin or placebo for 12 weeks at the start of anti-myeloma treatment. Follow-up was 4-weekly to 16 weeks and again at 1 year. The primary outcome was time to first febrile episode or death in the first 12 weeks from start of trial treatment. Secondary outcomes included number of infections, deaths, healthcare-associated organism carriage and invasive infections, and overall survival (OS). Findings: 977 patients were randomised (489 levofloxacin, 488 placebo). Primary events (febrile episodes, deaths, febrile episodes with death) in levofloxacin versus placebo arms were 19% vs 27% (87, 4, 4 vs 112, 15, 7), respectively; HR=0.66 (95% CI 0.51-0.86) p=0.002. There was no difference for new acquisitions of clostridium difficile, Methicillin-resistant Staphylococcus aureus and Extended Spectrum Beta Lactamase-positive (ESBL) Gram-negative coliforms when assessed up to 16 weeks. There was an OS benefit at 12 weeks (p=0.008) but not at one year (p=0.94). Interpretation: The addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths without increasing healthcare associated infections or carriage. Trial Registration Number: ISRCTN number: ISRCTN51731976 and EudraCT number: 2011-000366-35.Funding Statement: Funded by NIHR Health Technology Assessment Programme. 08/116/69.Declaration of Interests: None.Ethics Approval Statement: Approved by the UK Coventry & Warwickshire Multi-Research Ethics Committee on 29th July 2011. All patients provided written informed consent.

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.

Introduction and methods: Myeloma is a cancer with one of the longest pathways to diagnosis. This may be due to the non-specific nature of presenting symptoms and its' relative rarity. Early diagnosis initiatives have focused on the role of the primary physician. Despite concern that patients referred to non-haematology specialists may experience long diagnostic intervals, data remain sparse on pathways within hospital care. The TEAMM trial is a double-blind, placebo controlled multicentre UK trial of supportive care, investigating levofloxacin prophylaxis for 12 weeks from diagnosis to reduce infection, versus the risk of healthcare associated infection. Data were collected from patients within 14 days of starting anti-myeloma treatment, including symptoms attributable to myeloma, visits to their primary physician, first hospital department visited for these symptoms, and first visit to a haematologist, with corresponding dates. The relationship between diagnostic time intervals and the number of CRAB (hyperCalcaemia, Renal disease, Anaemia, Bone disease) features and ISS (International Staging System) were analysed by pathway into hospital care using the chi-square test for categorical variables or Wilcoxon/Kruskal-Wallis test for continuous variables as appropriate.

Abstract Background TEAMM (Tackling EArly Morbidity and Mortality in Myeloma) was a randomised, double-blind, placebo-controlled multi-centre phase III clinical trial assessing the benefits of antibiotic prophylaxis and its effect on healthcare associated infections. Infection in the first 12 weeks is the biggest cause of the high early death rate in myeloma. Levofloxacin is a quinolone antibiotic that is effective against the common bacterial infections in myeloma and taken once daily has proven efficacy as prophylaxis during therapy for other cancers. There has however been concern about the development of antibiotic resistance. We randomised the use of levofloxacin or placebo for 12 weeks to see if levofloxacin reduces febrile episodes and death in patients with newly diagnosed myeloma. Subjects were regularly screened for carriage of resistant organisms to detect if levofloxacin increases their carriage. Methods Patients were eligible if >21 years old with newly diagnosed symptomatic myeloma, intention to treat myeloma actively, and were +/- 14 days into a programme of anti-myeloma treatment. Patients were randomised to receive 500 mg levofloxacin or placebo tablets once daily for 12 weeks, dose adjusted for renal function. Patients were permitted to continue routine non-bacterial antimicrobial prophylaxis, including thrice weekly sulfamethoxazole-trimethoprim (SMZ-TMP) for pneumocystis. Faecal and throat samples were taken every 4 weeks to detect carriage of Clostridium difficile, MRSA and faecal ESBL-positive Gram-negative bacteria (ESBLGnB). The primary endpoint was the number of febrile episodes (defined as an oral temperature of ≥38°C treated with anti-infectives) and or death by any cause suffered in the first 12 weeks obtained using Kaplan-Meier curves censored at 12 weeks. Secondary outcomes included death, the number of clinically documented total infections, episodes of severe sepsis and suspected infections. Occurrence of febrile episodes was captured at clinic visits every 4 weeks up to 12 weeks. All patients were included in an intention to treat analyses. Results TEAMM recruited 977 patients between August 2012 and April 2016 from 92 centres within the UK. Median age was 67 years, 63% male, 76% had eGFR>50 ml/min, 54% had planned high dose chemotherapy with autologous-stem cell transplantation, 93% were ECOG performance status 0 to 2, 71% presented with bone disease. The primary endpoint showed a significant benefit for the use of levofloxacin with 134 of 488 patients (27%) on placebo reporting events (112 febrile episodes; 15 deaths; 7 febrile episodes and death) versus 95 of 489 patients (19%) on levofloxacin (87 febrile episodes; 4 deaths; 4 febrile episodes and death); hazard ratio (HR) 1.52 (95%CI 1.17-1.97) p=0.002, see figure 1. After 52 weeks there was no survival benefit between arms (p=0.94). Of the 586 total infections, there were 329 infections from 214 patients on the placebo arm and 257 infections from 189 patients on the Levofloxacin arm (chi-square=7.55,P-trend=0.006) with differences emerging after 4 weeks. C. difficile carriage at baseline was uncommon (7 of 785 subjects). Levofloxacin significantly reduced the number of recoded invasive gram-negative infections, but not the number of reported Gram positive infections. SMZ-TMP (315 patients) significantly reduced the number of febrile episodes and deaths and the effect of SMZ-TMP was additive with the effects of levofloxacin. Cox regression adjusting for baseline factors showed levofloxacin treatment (HR=1.47, 95%CI=1.10-1.96, p=0.009) and prophylactic SMZ-TMP (HR=1.75 (95%CI=1.26-2.43, p=0.0008) to be significant predictors for reduction of febrile episodes or death within the first 12 weeks of starting trial treatment, see table 1. There was no significant difference between the 2 arms for carriage or infection with C. difficile, MRSA and ESBLGnB. Conclusion Prophylactic use of 12 weeks levofloxacin for patients undergoing treatment for active myeloma significantly reduces febrile episodes and deaths without increasing healthcare associated infections or carriage of key nosocomial pathogens. The value of adding SMZ-TMP to levofloxacin and for periods greater than 12 weeks needs to be explored in future trials. Funding: Project funded by NIHR HTA programme (08/116/69). Views expressed are those of the authors and not those of the HTA programme, NIHR, NHS or the Department of Health. Disclosures Drayson: Abingdon Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Bowcock: Celgene: Other: Educational support; Amgen: Honoraria; Takeda: Other: educational support. Yong: Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.