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

Henrik Gregersen; Trung Do; Ida Bruun Kristensen; Ulf Christian Frølund; Niels Frost Andersen; Lene Kongsgaard Nielsen; Christen Lykkegaard Andersen; Tobias Wirenfeldt Klausen; Annette Juul Vangsted; Niels Abildgaard

doi:10.1186/s40164-018-0110-0

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

Henrik Gregersen^*, Trung Do, Ida Bruun Kristensen, Ulf Christian Frølund, Niels Frost Andersen, Lene Kongsgaard Nielsen, Christen Lykkegaard Andersen, Tobias Wirenfeldt Klausen, Annette Juul Vangsted, Niels Abildgaard

^*Corresponding author for this work

Department of Clinical Medicine

4 Citations (Scopus)

28 Downloads (Pure)

Abstract

Background: 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. Methods: Patients were randomized to receive tablet clarithromycin 500mg 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. Results: The 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. Conclusion: The 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.

Original language	English
Article number	18
Journal	Experimental Hematology & Oncology
Volume	7
Issue number	1
DOIs	https://doi.org/10.1186/s40164-018-0110-0
Publication status	Published - 2018

Keywords

Adverse drug event
Bortezomib
Clarithromycin
Double blind study
Induction chemotherapy
Multiple myeloma

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Gregersen, H., Do, T., Kristensen, I. B., Frølund, U. C., Andersen, N. F., Nielsen, L. K., Andersen, C. L., Klausen, T. W., Vangsted, A. J., & Abildgaard, N. (2018). 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. Experimental Hematology & Oncology, 7(1), Article 18. https://doi.org/10.1186/s40164-018-0110-0

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. / Gregersen, Henrik; Do, Trung; Kristensen, Ida Bruun et al.
In: Experimental Hematology & Oncology, Vol. 7, No. 1, 18, 2018.

Research output: Contribution to journal › Journal article › Research › peer-review

Gregersen, H, Do, T, Kristensen, IB, Frølund, UC, Andersen, NF, Nielsen, LK, Andersen, CL, Klausen, TW, Vangsted, AJ & Abildgaard, N 2018, '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', Experimental Hematology & Oncology, vol. 7, no. 1, 18. https://doi.org/10.1186/s40164-018-0110-0

Gregersen H, Do T, Kristensen IB, Frølund UC, Andersen NF, Nielsen LK et al. 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. Experimental Hematology & Oncology. 2018;7(1):18. doi: 10.1186/s40164-018-0110-0

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abstract = "Background: 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. Methods: Patients were randomized to receive tablet clarithromycin 500mg 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. Results: The 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. Conclusion: The 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.",

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author = "Henrik Gregersen and Trung Do and Kristensen, {Ida Bruun} and Fr{\o}lund, {Ulf Christian} and Andersen, {Niels Frost} and Nielsen, {Lene Kongsgaard} and Andersen, {Christen Lykkegaard} and Klausen, {Tobias Wirenfeldt} and Vangsted, {Annette Juul} and Niels Abildgaard",

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T1 - 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

AU - Gregersen, Henrik

AU - Do, Trung

AU - Kristensen, Ida Bruun

AU - Frølund, Ulf Christian

AU - Andersen, Niels Frost

AU - Nielsen, Lene Kongsgaard

AU - Andersen, Christen Lykkegaard

AU - Klausen, Tobias Wirenfeldt

AU - Vangsted, Annette Juul

AU - Abildgaard, Niels

PY - 2018

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N2 - Background: 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. Methods: Patients were randomized to receive tablet clarithromycin 500mg 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. Results: The 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. Conclusion: The 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.

AB - Background: 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. Methods: Patients were randomized to receive tablet clarithromycin 500mg 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. Results: The 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. Conclusion: The 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.

KW - Adverse drug event

KW - Bortezomib

KW - Clarithromycin

KW - Double blind study

KW - Induction chemotherapy

KW - Multiple myeloma

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DO - 10.1186/s40164-018-0110-0

M3 - Journal article

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AN - SCOPUS:85051599257

SN - 2162-3619

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