Prophylaxis in Newly Diagnosed Myeloma Reduces Complications

Alexander M. Castellino, PhD

November 05, 2019

Treatment for multiple myeloma has made significant strides in recent years, with a plethora of new drugs now available, but little attention has been given to supportive care measures, which can also improve outcomes.

A new study shows the impact this can have as anti-infectious prophylaxis with levofloxacin reduced the risk of febrile episodes or death by one third among patients newly diagnosed with multiple myeloma.

The results come from the TEAMM study and were published online October 23 in Lancet Oncology.

Newly diagnosed myeloma patients are at great risk of morbidity and mortality from infections, study author Mark T. Drayson, MBChB, PhD, from the University of Birmingham, United Kingdom, told Medscape Medical News.

The study showed that prophylaxis with levofloxacin reduces the incidence of febrile episodes, but it also showed that it did not result in an increase in antibiotic resistance. This is a concern that has hampered the use of prophylaxis in the clinic, he said.

However, the study showed acquisition rates for Clostridium difficile, ESLB (extended-spectrum b-lactamase, and MRSA (methicillin-resistant Staphylococcus aureus) in patients receiving levofloxacin were similar to those who received placebo.

Based on the data from TEAMM, Drayson said that anti-infectious prophylaxis is now routinely offered to all patients who receive anti-myeloma treatment.

In an accompanying commentary, Karthik Ramasamy, MBBS, PhD, from the Oxford University Hospitals NHS Foundation Trust in the UK, commended the TEAMM researchers for drawing focus to the area of supportive care in myeloma.

"This study is timely in showing that fixed-duration levofloxacin prophylaxis reduces febrile infections and early deaths in patients with myeloma during induction chemotherapy," he writes.

However, considering the rapidly changing treatment landscape in myeloma, additional confirmatory studies are needed, he said.

TEAMM Study Details

TEAMM was a prospective, multicenter, double-blind, placebo-controlled randomized study in newly diagnosed patients on anti-myeloma therapy undertaken in 93 UK hospitals. Patients were randomly assigned to anti-infective prophylaxis with levofloxacin 500 mg daily (n = 489) or placebo (n = 488) for 12 weeks.

Patients enrolled in the study reflected those seen in clinical practice, say the authors. Performance status was not a specification in the study and patients receiving any anti-myeloma treatment were enrolled. Patients were treated with regimens based on thalidomide (43%), bortezomib [Velcade, Takeda] (31%) or lenalidomide [Revlimid, Celgene] (15%).   

The primary outcome was either the first febrile episode (≥ 38°C/100.4°F) that required anti-infective treatment or early death (within the 12-week window of treatment).

Significantly fewer febrile episodes or death were reported in patients receiving levofloxacin (19%) compared with those on placebo (27%) (P = .0018), which corresponds to a 34% reduced risk of infection, note the authors.

After controlling for baseline characteristics, levofloxacin treatment emerged as the most important factor in reducing febrile episodes.

Drayson and colleagues also reported fewer hospital and intensive care unit admissions for infection in patients receiving levofloxacin, suggesting a reduced utilization of health care resources.

However, with a median follow up of 12 months, the reduced febrile episode rates did not translate into survival benefits: the 12-month survival was 90% with levofloxacin  and 91% for placebo (P = .94).

"Levofloxacin might have kept non-responding patients alive longer than placebo patients and once the treatment stopped non-responders began to die," the authors comment.

In his commentary, Ramasamy adds: "This result could be partly explained by the high number of patients who had poorly controlled myeloma in this trial."  

Questions Arising

Ramasamy also comments that the treatment of myeloma has progressed so rapidly in recent years that the way that patients were treated in this trial has already changed.

For example, monoclonal antibody-based combinations with daratumumab (Darzalex, Janssen) have recently been introduced, and results with these combinations report an increase in grade 3 or 4 infections.

"These newer agents are markedly immunosuppressive and administered for prolonged periods, and so levofloxacin prophylaxis is likely to be important in these patients," Drayson told Medscape Medical News.

He suggested that myeloma patients who have relapsed would also likely benefit from levofloxacin prophylaxis without developing significant antibiotic resistance.

Longer Period of Prophylaxis?

In this trial, levofloxacin prophylaxis was administered for 12 weeks in newly diagnosed patients.

But the risk of infection remains high during the first year of diagnosis, Drayson and colleagues note.

"A continuing risk beyond 12 weeks raises the question of whether…12 months of prophylaxis might be beneficial" and whether this would translate to improved survival, they comment.

Also, if patients were to receive levofloxacin for a longer period of time, it may translate to patients who did not respond to first-line therapy living long enough to respond to second-line therapy.  

Drayson told Medscape Medical News that the team is now planning a trial of a year's worth of levofloxacin prophylaxis with or without co-trimoxazole to see if long-term survival can be increased. This design is based on observations from TEAMM, in which almost one third of patients also received low-dose co-trimoxazole to prevent Pneumocystis jirovecii pneumonia, and this was associated with a 41% reduced risk of febrile episodes or death.

"Since co-trimoxazole use was unrandomised and determined by the treating centre, these findings…should be interpreted with caution," Drayson and colleagues write. At present, they note that routine treatment with co-trimoxazole is not warranted.

Drayson reports personal fees from Abingdon Health, outside the submitted work. Conflict of interest for other study authors is found in the original article. Ramasamy reports research grants, advisory board fees, and speaker fees from Celgene, Takeda, Janssen, and Amgen, and advisory board fees from Sanofi, AbbVie, and Oncopeptides, outside the published work.

Lancet Oncology. Published online October 23, 2019. Abstract, Editorial

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