A randomized placebo-controlled phase II study of clarithromycin or placebo combined with VCD induction therapy prior to high-dose melphalan with stem cell support in patients with newly diagnosed multiple myeloma

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)

Clarithromycin added to bortezomib‐cyclophosphamide‐dexamethasone impairs health‐related quality of life in multiple myeloma patients

“…Thus, the reduced HRQoL could be a result of increased biological effect of bortezomib in the clarithromycin group. 13 Clarithromycin has been used in other treatment regimens for MM often in combination with lenalidomide and lowdose dexamethasone, which is found to have favourable toxicity profile. 14 This discrepancy in AE findings compared to our study supports the explanation of being caused by the pharmacokinetic interaction between bortezomib and clarithromycin, when those two drugs are administrated in parallel.…”

“…However, no serious cardiovascular events were reported during the study. 13 In clinical studies, AEs are traditionally collected as described in CTCAE guideline by clinicians. 24 Drug efficacy and toxicity profile analyses are included in the process where a given drug is considered for approval by the FDA and EMA.…”

“…Study details have been published previously. 13 Newly diagnosed transplant-eligible MM patients with treatment-demanding disease according to the International Myeloma Working Group criteria were eligible for inclusion. 15 The patients were randomized (1:1 ratio) to treatment with clarithromycin 500 mg orally twice daily or a matching placebo tablet for 63 days in combination with VCD induction therapy.…”

“…12 The Danish Myeloma Study Group (DMSG) initiated a randomized, placebo-controlled double-blinded phase II study to investigate the efficacy and safety of adding clarithromycin to bortezomib-cyclophosfamide-dexamethason (VCD) induction therapy prior to HDT in newly diagnosed MM patients. 13 Clarithromycin in combination with lenalidomide and low-dose dexamethasone is been found to be an effective treatment regimen with manageable side effects in treatment naïve symptomatic MM patients. 14 The rationale for this study, entitled the CLAIM study, was to test these previous findings using a randomized placebo-controlled study design with addition of patient-reported HRQoL captured by validated PRO questionnaires.…”

“…Response data did not suggest any effect of adding clarithromycin to the VCD regimen. 13 The primary objective of this analysis was to evaluate the patient-reported HRQoL in patients receiving clarithromycin added to the VCD induction therapy. The secondary objective was to compare patient-reported toxicities to AEs reported by clinicians.…”