Abstract
BackgroundThe objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib–cyclophosphamide–dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy.MethodsPatients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo.ResultsThe study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5–64.7) and in 16 patients (51.6%, 33.1–69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group.ConclusionThe study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy.Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9)
Highlights
The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib–cyclophosphamide–dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy
In a study by Niesvizky et al the combination of clarithromycin, 500 mg twice daily with lenalidomide and dexamethasone led to partial response or better in 90% of treatment-naive patients with symptomatic multiple myeloma [4]
Gay et al conducted a case-matched analysis based on the Niesvizky study and compared 72 patients treated with clarithromycin, lenalidomide and dexamethasone with an equal number of patients seen at the Mayo Clinic only treated with lenalidomide and dexamethasone [5]
Summary
The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib–cyclophosphamide–dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy. Clarithromycin has been proposed as a potentially good candidate for addition to multiple myeloma therapy in pursuit of synergistic effects [1]. This concept is based on the favorable toxicity profile of clarithromycin when used in the treatment of infections, the very low cost and response data from combination with immunomodulatory drugs (IMiDs) in phase II trials and in one case-matched study [2,3,4,5]. In a study by Niesvizky et al the combination of clarithromycin, 500 mg twice daily with lenalidomide and dexamethasone led to partial response or better in 90% of treatment-naive patients with symptomatic multiple myeloma [4]. There are so far no data from randomized controlled studies to support an effect of clarithromycin in multiple myeloma
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