Clarithromycin plus lenalidomide and dexamethasone for the treatment of multiple myeloma (MM) did not offer a survival benefit compared with standard treatment, according to a phase 3 trial.
“Although case-control analyses have suggested an additive value with the association of clarithromycin to continuous lenalidomide and dexamethasone, there are not phase 3 trials confirming these results,” wrote the study authors. The findings from this trial were published in Blood Cancer Journal.
Clarithromycin for Multiple Myeloma
Clarithromycin is an antibiotic previously found to have immunomodulatory properties, according to the authors. The investigators tested this drug in the multi-center, open label GEM-CLARIDEX trial, which enrolled 286 patients aged ≥65 years with newly diagnosed MM who were ineligible for autologous hematopoietic cell transplantation (AHCT).
Patients were randomized 1:1 to the all-oral regimen of clarithromycin plus lenalidomide 25 mg and dexamethasone 40 mg (C-Rd) or lenalidomide and dexamethasone alone (Rd). Clarithromycin was dosed at 500 mg per 12 hours continuously. Reduced doses of Rd were administered to patients with impaired creatinine clearance or patients aged ≥75 years, respectively. Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and secondary endpoints included response rates and duration, time to disease progression, overall survival, and safety and tolerability.
Median follow-up was 19 months. At time of data cutoff, three-quarters of patients in the C-Rd group and 57.3% of patients in the Rd group had discontinued treatment. Progressive disease was the most common reason for treatment discontinuation (C-Rd, 31.4%; Rd, 12.2%). Median duration for C-Rd was 15.0 months (range, 0.2–44), compared with 15.9 months (range, 0.4–46) for Rd.
No PFS Benefit for C-Rd Versus Rd
At median follow-up, disease progression or death occurred in 49.6% of patients (n = 71) in the C-Rd group and 42.6% of the Rd group (n = 61). Median PFS in the C-Rd versus Rd groups was 23 months (95% confidence interval [CI], 15.3–30.6) and 29 months (95% CI, 22.4–35.5), respectively. The hazard ratio for disease progression or mortality in the clarithromycin group was 1.293 (95% CI, 0.92–1.82, P = 0.14).
The overall response rate to C-Rd and Rd was 71.5% and 76.4%, respectively. More patients in the C-Rd group achieved a complete response (CR) or better compared to the Rd group (22.6% vs. 14.4%, P = 0.048). There was no significant differences in minimal residual disease (MRD) negativity between groups.
The most common grade ≥3 adverse events (AEs) were neutropenia and infections. Rates of AEs were similar between groups, however death due to toxicity was more common in the C-Rd group compared with the control (72% vs. 55% of deaths; P = 0.09).
“The addition of clarithromycin to Rd in untreated transplant-ineligible [patients with] MM does not improve PFS despite increasing the ≥CR rate due to the higher number of toxic deaths in the C-Rd arm,” the authors concluded. “Side effects related to overexposure to steroids due to its delayed clearance induced by clarithromycin in this elderly population could explain these results.”