The addition of clarithromycin to treatment with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma did not significantly improve progression-free survival in a phase 3 trial.
It contrasts with previous case-control analyses which had suggested better response rates when including the macrolide antibiotic to the regimen in patients who were ineligible for stem cell transplant or high-dose chemotherapy.
But the findings may be explained by a higher proportion of toxic deaths in the clarithromycin group in the older patients in the trial, the Spanish researchers said.
In the trial of 275 patients randomly assigned to lenalidomide and dexamethasone with or without clarithromycin, there was a significantly higher rate of complete response in those also given the antibiotic (22.6% vs 14.4%, p = 0.048).
But the median progression free survival was not significantly different between the two groups of patients at 23 months in the clarithromycin group compared with 29 months with the standard regimen.
Overall at an average 19 months follow up disease progression or death was observed in 132 patients – 49.6% in the clarithromycin group and 42.6% in the control group – a comparable figure to that reported in other studies of newly diagnosed patients ineligible for stem cell transplant, the researchers reported.
Writing in Blood Cancer Journal, they said the findings contrasts with previous retrospective and single-arm studies that had reported better outcomes when clarithromycin was combined with immunomodulatory drugs, either thalidomide, lenalidomide or pomalidomide, and highlights the importance of phase 3 trials.
More than half the patients in the trial were over the age of 75 years and a more in-depth analysis showed a shorter median progression free survival in those who also had clarithromycin yet no difference in time to progression.
While the most common severe adverse events of neutropenia and infections were similar between the two groups, the percentage of toxic deaths was higher in the clarithromycin group which were mostly infection-related and concentrated in the over 75s, they reported.
The higher-treatment related deaths in older patients in the trial could go some way to explaining their findings, they pointed out.
“In this elderly population, overexposure to steroids due to the delayed clearance induced by clarithromycin together with a lower treatment compliance could explain our results,” they concluded.
“Further investigations modifying the dose of both clarithromycin and steroids based on age and frailty status could be of interest to exploit the benefits of this combination.”