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

Abstract

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 coordination 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.

Antibiotic prophylaxis for patients with newly diagnosed multiple myeloma: Systematic review and meta‐analysis

“…Two studies reported the incidence of severe infections, 7,8 whereas one study did not report on the incidence of severe infections, instead reporting on febrile vs non-febrile infections, and episodes of severe sepsis. 9 The incidence of severe infection, defined as a Grade III or Grade IV infection including hospitalization, was numerically lower for the patients that received antibiotics vs those that did not; however, this did not reach statistical significance (8.0% vs 14.8%, RR: 0.57, 95% CI 0.30-1.06, P = .08, I 2 = 0%) ( Figure 3).…”

“…One study reported a lower incidence of hospitalization in the intervention group vs control group (88 vs 114 events, P value not provided). 9 The sensitivity analysis for each outcome was consistent when alternate model using fixed effect and Mantel-Haenszel method was applied. al was either an immunomodulatory drug (thalidomide in 43%, lenalidomide in 15%) or proteasome-based regimen (bortezomib in 31%).…”

“…8,9 Thus, in patients receiving novel treatments, a benefit was seen with prophylactic antibiotics in reducing febrile infections and death, but no benefit was seen in reduction of infection risk in a trial where patients tended to receive traditional cytotoxic chemotherapy. 8,9 Furthermore, local antibiotic resistance patterns may also play a significant role in determining these results, especially considering It must be noted that none of the three clinical trials reported the incidence of neutropenia for their cohorts of patients. [7][8][9] This is an important factor as it is well known that treatment for MM can cause neutropenia 18 and that antibiotic prophylaxis for prolonged neutropenia leads to a benefit for those patients.…”

Multiple myeloma current treatment algorithms

“…We recommend prophylaxis against pneumocystis jiroveci for all patients on dexamethasone. We also recommend levofloxacin daily for the first two cycles in all patients with newly diagnosed MM 28 .…”

Recent Advancements in Hematology: Knowledge, Methods and Dissemination, Part 1

“…Susceptibility to infection is primarily the consequence of acquired tumor-related deficiency of both humoral and cellular immunity. The publication by Drayson et al [6] in Lancet Oncology is a welcomed focus on supportive care in myeloma. They present the findings that showed that 12 weeks of fixed-duration levofloxacin prophylaxis reduced the occurrence of febrile episodes and deaths with a hazard ratio [HR] 0.66, (95% CI 0.51-0.86; p = 0.0018) when levofloxacin was delivered prophylactically compared to placebo.…”