Myeloma: diagnosis and management

Study 1

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

Background

Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5,500 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. The study 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 healthcare-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. Patients were randomly assigned (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 August 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 (interquartile range [IQR] 8 to 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 [HR] 0.66, 95% confidence interval [CI] 0.51 to 0.86; p=0.0018). 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] were in the levofloxacin group and 289 [48%] were in the placebo group). Serious adverse events were similar between the 2 groups except for 5 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 healthcare-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy.

Assessment of the impact on NICE's guideline on myeloma

The TEAMM trial is a prospective, multicentre, double-blind, placebo-controlled randomised trial of antibiotic prophylaxis in patients with myeloma. It is the first trial of this size and design to show that prophylactic levofloxacin could be used for newly diagnosed myeloma patients undergoing the first 12 weeks of anti-myeloma therapy, to reduce febrile episodes and deaths compared with placebo without increasing healthcare-associated infections. The trial was designed to map onto current standard practice in the UK.

A limitation of the study is that the patient population recruited were generally younger and had fewer comorbidities than likely 'real-world' patients, leading to a small total number of deaths. The authors also report that there may be additional mechanisms underlying the benefits of levofloxacin prophylaxis other than a reduction in infection. For example, a change in the microbiome might have contributed to a reduction in inflammation. Further in-depth studies on the microbiome are needed to evaluate this.

A further limitation was the high number of withdrawals, despite the low toxicity of levofloxacin. Around half of the withdrawals occurred in the first 4 weeks. Patients had to collect stool samples every 4 weeks, take their temperatures daily, and fill in a diary, which might have been burdensome. Forty percent of patients were also in a trial of active therapy (Myeloma XI) which may have been prioritised over the TEAMM trial and been another reason for withdrawal. It is important to note that the patient population was 91% white, suggesting further research should be done with individuals from different ethnicity backgrounds.

This RCT provides some good quality evidence on the effectiveness and safety of antibiotic prophylaxis, with levofloxacin, to reduce febrile episodes and death in patients with newly diagnosed myeloma. However, uncertainty remains around whether it would be more appropriate to wait until a patient has an infection before prescribing antibiotics due to concerns around side effects and antibiotic resistance. The use of levofloxacin prophylaxis for periods greater than 12 weeks also needs to be explored in future trials. It is unclear whether this single RCT provides sufficient evidence to warrant an update to the NICE guideline.

Study 2

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

Objective

To ascertain the benefit of prophylactic antibiotics for patients with newly diagnosed multiple myeloma (MM), given that clinical trials evaluating this have had conflicting results.

Methods

A systematic review and meta-analysis was performed evaluating the use of prophylactic antibiotics in patients with MM and its impact on infection risk and mortality.

Results

Across 3 included studies, a total of 664 patients received antibiotics and 650 patients received no antibiotics. The overall incidence of infection within 3 months was lower for the antibiotic group compared to placebo (18.4% versus 23.4%, risk ratio [RR]: 0.79, 95% CI 0.62 to 1.00, p=.05, I²=6.5%). There was no difference in mortality in the first 3 months (1.5% versus 3.5%, RR: 0.47, 95% CI 0.17 to 1.27, p=.60, I²=28.1%).

Conclusion

Antibiotic prophylaxis for a finite duration can decrease the overall incidence of infection within the first 3 months following diagnosis. This does not lead to a decrease in mortality. Further data on antibiotic resistance patterns, toxicity, healthcare expenditures, and the impact of antibiotics on subsequent therapies can assist providers in helping make decisions on prophylactic antibiotics with their patients.

Assessment of the impact on NICE's guideline on myeloma

This is the first meta-analysis to evaluate the impact of prophylactic antibiotics in myeloma patients in decreasing the risk of infection and mortality. The results indicate that antibiotic prophylaxis for 2 to 3 months following diagnosis leads to a decrease in the incidence of infections for patients with myeloma. However, this decrease was just at the threshold of statistical significance. Furthermore, there was no decrease in mortality noted and it is unknown if the incidence of complications may increase if prophylaxis was extended for a longer period than 3 months.

There was considerable variability in findings across the 3 RCTs included in this meta-analysis, which led to heterogeneity in the results. The meta-analysis consists of 2 small RCTs (Oken et al. 1996 [54 patients] and Vesole et al. 2012 [212 patients]), which were included in the original NICE guideline in 2016, and a third larger, double blind randomised, placebo-controlled trial (TEAMM trial, 977 patients).

The results of the TEAMM trial differ significantly from those in Vesole et al. Vesole et al. reported negative results with no significant impact on infection overall, while the TEAMM trial found that levofloxacin prophylaxis led to a reduction in febrile episodes and death at 12 weeks. However, a comparison of the populations in the 2 studies was not possible due to differences in their primary endpoints and selective reporting of variables. The duration of antibiotics differed with 2 months used in Vesole et al. and 3 months in the TEAMM trial, and the data in Vesole et al. may not be applicable to today's patient population which rarely receives cytotoxic chemotherapy. Vesole et al. also did not report on toxicities resulting from antibiotic use. Furthermore, local antibiotic resistance patterns in the UK and United States may also play a significant role in the results.

Another point to consider is that there is increasing evidence that the gut microbiome is an important determinant in patients' response to immunotherapy. Given that immunotherapy may be a current treatment option for people with relapsed myeloma, caution is needed when considering antibiotic prophylaxis, as the impact this may have on subsequent immunotherapies is unknown.

The heterogeneity of the studies is an important limitation of this meta-analysis. Further research is needed on antibiotic resistance, toxicity, mortality, healthcare expenditures, and the impact of antibiotics on subsequent therapies. This meta-analysis therefore does not provide sufficient evidence to warrant an update to the NICE guideline.