Adding clarithromycin to lenalidomide plus dexamethasone improved the response rate in patients with multiple myeloma (MM), compared with lenalidomide and dexamethasone (Rd) alone. However, this higher efficacy did not translate to improved survival, particularly among older patients, and did not meet its primary objective, lead investigator Noemi Puig, MD, PhD, from the Hospital Universitario de Salamanca in Spain, reported at the 2019 ASH Annual Meeting.
Clarithromycin appears to have immunomodulatory effects and direct antineoplastic properties, Dr. Puig noted in her presentation, and previous research has shown that adding clarithromycin to standard Rd treatment for patients with MM who are not eligible for autologous hematopoietic cell transplantation is safe and enhances response.
The open-label, randomized, phase III GEM-Claridex trial included 286 patients with previously untreated MM. Patients were randomized 1:1 to receive Rd (lenalidomide 25 mg daily plus dexamethasone 40 mg on days 1, 8, 15, and 22) with or without clarithromycin 500 mg daily. Treatment continued until disease progression or unacceptable toxicity.
Participants’ median age was 76 years (range = 65-93). About one-third of patients (36.8%) had International Staging System stage 3 disease, and 15.6% had high-risk cytogenetic abnormalities.
During a median follow-up of 16 months (range = 1-47), patients received a median of 10 treatment cycles (range = 1-40) in the Rd group and 8 cycles (range = 1-40) in the clarithromycin group. All patients experienced at least one adverse event (AE), and most experienced at least one grade ≥3 treatment-emergent AE: 82.5% (n=118) in the Rd group and 81.8% (n=117) in the clarithromycin group. There were no significant differences in rates of hematologic AEs, except for anemia, which was more frequently reported in the Rd arm (17.4% vs. 14.6%; p=0.04).
A substantial number of patients discontinued treatment: 66 (46.2%) in the Rd group and 91 (63.2%) in the clarithromycin group. Discontinuations were mostly due to disease progression:
- disease progression: 31 (47%) in the Rd arm and 26 (28.6%) in the clarithromycin group
- AE: 12 (18.2%) and 16 (17.6%)
- treatment-related deaths: 8 (12.1%) and 21 (23.1%)
- other reasons: 15 (22.7%) and 28 (24.2%)
The higher number of treatment-related deaths in the clarithromycin group point to the failure of clarithromycin to improve progression-free survival (PFS), the study’s primary endpoint. While clarithromycin was associated with higher objective response and complete response rates (TABLE), there were no significant differences in median PFS: 23 months with Rd versus not reached for clarithromycin (p=0.12). Most of these deaths were related to infections, the authors noted, and mainly affected the group of patients older than 75.
In the 129 patients younger than 75, though, Dr. Puig noted that, at 20 months, 61% and 60% of patients in the Rd and clarithromycin group, respectively, were alive and free from progressive disease. Of those ≥75 years, there was a significant benefit for PFS in the Rd arm: 28 months vs. 19 months (hazard ratio = 1.5; p=0.07).
Overall survival also was not reached and not significantly different between the two treatment arms (p value not reported).
Given the findings that the higher efficacy of clarithromycin plus Rd was not associated with a better PFS, particularly in older patients, Dr. Puig concluded that “clarithromycin could be added to Rd in patients with newly diagnosed MM who are younger than 75 years and not candidates for transplant, but dose reductions and anti-infectious prophylaxis should be considered.” Though the trial was not designed to determine why the addition of clarithromycin failed to prolong survival, she added that the interaction between steroids and clarithromycin could potentially explain these results.
Puig N, Hernández MT, Dachs LR, et al. Randomized trial of lenalidomide and dexamethasone versus clarithromycin, lenalidomide and dexamethasone as first line treatment in patients with multiple myeloma not candidates for autologous stem cell transplantation: results of the GEM-Claridex clinical trial. Abstract #694. Presented at the 2019 American Society of Hematology Annual Meeting, December 9, 2019; Orlando, FL.
TABLE. Response to Treatment With Lenalidomide and Dexamethasone, With and Without Clarithromycin
|Clarithromycin + Rd
|Objective response rate||74.5%||81%||Not reported|
|Complete response, n (%)||16 (11)||29 (21)||0.037|
|Very good partial response, n (%)||37 (26)||47 (35)||0.007|
|Partial response, n (%)||52 (37)||33 (25)||Not reported|
|Stable disease, n (%)||35 (25)||24 (18)||Not reported|
|Progressive disease, n (%)||1 (0.7)||1 (0.7)||Not reported|
|Rd = lenalidomide plus dexamethasone|