TY - JOUR
T1 - Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI)
T2 - a randomised, double-blind, multicentre, phase 3 trial
AU - Kumar, Shaji K.
AU - Harrison, Simon J.
AU - Cavo, Michele
AU - de la Rubia, Javier
AU - Popat, Rakesh
AU - Gasparetto, Cristina
AU - Hungria, Vania
AU - Salwender, Hans
AU - Suzuki, Kenshi
AU - Kim, Inho
AU - Punnoose, Elizabeth A.
AU - Hong, Wan Jen
AU - Freise, Kevin J.
AU - Yang, Xiaoqing
AU - Sood, Anjla
AU - Jalaluddin, Muhammad
AU - Ross, Jeremy A.
AU - Ward, James E.
AU - Maciag, Paulo C.
AU - Moreau, Philippe
N1 - Funding Information:
AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis and collection, and verification and interpretation of data, and the writing, review, and approval of the publication. Medical writing assistance was provided by Allison Cherry and funded by AbbVie. RP is supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. SKK has received grants from the National Institute of Health. We thank the patients and their families, study coordinators, and support staff.
Funding Information:
AbbVie and Genentech provided financial support for the study and participated in the design, study conduct, analysis and collection, and verification and interpretation of data, and the writing, review, and approval of the publication. Medical writing assistance was provided by Allison Cherry and funded by AbbVie. RP is supported by the National Institute for Health Research, University College London Hospitals Biomedical Research Centre. SKK has received grants from the National Institute of Health. We thank the patients and their families, study coordinators, and support staff.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/12
Y1 - 2020/12
N2 - Background: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m2 subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597. Findings: Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6–21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3–not estimable) with venetoclax versus 11·5 months (9·6–15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44–0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related. Interpretation: The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option. Funding: AbbVie and Genentech.
AB - Background: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods: In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m2 subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597. Findings: Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6–21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3–not estimable) with venetoclax versus 11·5 months (9·6–15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44–0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related. Interpretation: The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option. Funding: AbbVie and Genentech.
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U2 - 10.1016/S1470-2045(20)30525-8
DO - 10.1016/S1470-2045(20)30525-8
M3 - Article
C2 - 33129376
AN - SCOPUS:85096021122
SN - 1470-2045
VL - 21
SP - 1630
EP - 1642
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 12
ER -