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A PHASE 1B STUDY OF VENETOCLAX COMBINED WITH BORTEZOMIB AND DEXAMETHASONE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA
Author(s):
Philippe Moreau
,
Philippe Moreau
Affiliations:
CHU de Nantes, Hotel Dieu-HME,Nantes,France
Asher Chanan-Khan
,
Asher Chanan-Khan
Affiliations:
Mayo Clinic,Jacksonville,United States
Andrew W. Roberts
,
Andrew W. Roberts
Affiliations:
Royal Melbourne Hospital and Walter and Eliza Hall Institute of Medical Research, Cancer and Hematology Division,Melbourne,Australia
Amit B. Agarwal
,
Amit B. Agarwal
Affiliations:
The University of Arizona Cancer Center,Tuscon,United States
Thierry Facon
,
Thierry Facon
Affiliations:
CHRU Lille, Hopital Huriez,Lille,France
Shaji Kumar
,
Shaji Kumar
Affiliations:
Mayo Clinic,Rochester,United States
Cyrille Touzeau
,
Cyrille Touzeau
Affiliations:
CHU de Nantes, Hotel Dieu-HME,Nantes,France
Jaclyn Cordero
,
Jaclyn Cordero
Affiliations:
AbbVie, Inc.,North Chicago,United States
Jeremy Ross
,
Jeremy Ross
Affiliations:
AbbVie, Inc.,North Chicago,United States
Wijith Munasinghe
,
Wijith Munasinghe
Affiliations:
AbbVie, Inc.,North Chicago,United States
Jia Jia
,
Jia Jia
Affiliations:
AbbVie, Inc.,North Chicago,United States
Ahmed H. Salem
,
Ahmed H. Salem
Affiliations:
AbbVie, Inc.,North Chicago,United States
Joel Leverson
,
Joel Leverson
Affiliations:
AbbVie, Inc.,North Chicago,United States
Paulo Maciag
,
Paulo Maciag
Affiliations:
AbbVie, Inc.,North Chicago,United States
Maria Verdugo
,
Maria Verdugo
Affiliations:
AbbVie, Inc.,North Chicago,United States
Simon J. Harrison
Simon J. Harrison
Affiliations:
Peter MacCallum Cancer Centre,Melbourne,Australia
(Abstract release date: 05/18/17) EHA Library. Moreau P. 06/24/17; 181747; S460
Prof. Philippe Moreau
Prof. Philippe Moreau
Contributions
PDF Abstract
Abstract

Abstract: S460

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 17:00 - 17:15

Location: Hall A

Background
Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecular inhibitor of BCL-2. When combined, VEN can enhance the activity of bortezomib in multiple myeloma (MM) cell lines and xenograft models.

Aims
The objectives of the study are to evaluate safety and preliminary efficacy of VEN with bortezomib and dexamethasone in relapsed/refractory (RR) MM.

Methods
Phase 1b study of patients (pts) with R/R MM who received daily VEN (50–1200 mg for dose escalation cohorts; 800 mg in safety expansion) with standard bortezomib (1.3 mg/m2 SC) and dexamethasone (20 mg PO).

Results
As of 19Aug2016, 66 pts were enrolled. Median age was 64 years; 9 (14%) pts had t(11;14), 5 (8%) had t(4;14), 15 (23%) had del(17p), and 30 (45%) had del(13q) abnormalities. Median number of prior therapies was 3 (range: 1–13), with 39% of pts refractory to prior bortezomib, 14% to carfilzomib, 53% to lenalidomide, and 21% to pomalidomide.

Median time on study was 5.9 months (range: 0.3–29.8). Forty-six (70%) pts discontinued, with 36 due to disease progression (PD). Common AEs in ≥30% of pts were diarrhea (46%), constipation (41%), thrombocytopenia (39%), nausea (38%), peripheral neuropathy (33%), and insomnia (32%). Common grade 3/4 AEs in ≥10% of pts were thrombocytopenia (29%), anemia (15%) and neutropenia (14%). Serious AEs in ≥2 pts were febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension. Dose-limiting toxicities were grade 3 cardiac failure in the 300mg cohort (possibly related to dexamethasone) and grade 3 thrombocytopenia during the first cycle in the safety expansion. No events of laboratory or clinical TLS were reported. Four deaths were due to PD and 1 due to respiratory syncytial virus infection.
Overall response rate (ORR) for all pts was 67% (44/66); 28 (42%) pts achieved very good partial response (VGPR) or better (3 stringent complete response [sCR], 10 CR, 15 VGPR). Pts non-refractory to prior proteasome inhibitors (PI) or immunomodulatory drugs (IMiDs) had higher ORR than refractory pts (PI, 92% vs 32%; IMiDs, 82% vs 57%). Among pts refractory to any 2 or more (n=15), 3 or more (n=7), or all 4 (n=4) prior therapies (bortezomib, carfilzomib, lenalidomide, pomalidomide), ORR was 40%, 43%, and 25%, respectively. Median time to progression (~10 vs 3 months) and duration of response (~10 vs 7 months) were longer for pts not refractory to any of these therapies versus refractory pts. ORR for pts with or without cytogenetic abnormalities, respectively, was as follows: 78% vs 65% for t(11;14), 60% vs 67% for t(4;14), 47% vs 73% for del(17p), and 63% vs 69% for del(13q).

Conclusion
VEN combined with bortezomib and dexamethasone has an acceptable safety profile with promising anti-myeloma activity, and the highest response rates were observed in R/R MM pts who were not refractory to PI or IMiDs. These data support the ongoing phase 3 trial with this regimen in R/R MM.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Abstract: S460

Type: Oral Presentation

Presentation during EHA22: On Saturday, June 24, 2017 from 17:00 - 17:15

Location: Hall A

Background
Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecular inhibitor of BCL-2. When combined, VEN can enhance the activity of bortezomib in multiple myeloma (MM) cell lines and xenograft models.

Aims
The objectives of the study are to evaluate safety and preliminary efficacy of VEN with bortezomib and dexamethasone in relapsed/refractory (RR) MM.

Methods
Phase 1b study of patients (pts) with R/R MM who received daily VEN (50–1200 mg for dose escalation cohorts; 800 mg in safety expansion) with standard bortezomib (1.3 mg/m2 SC) and dexamethasone (20 mg PO).

Results
As of 19Aug2016, 66 pts were enrolled. Median age was 64 years; 9 (14%) pts had t(11;14), 5 (8%) had t(4;14), 15 (23%) had del(17p), and 30 (45%) had del(13q) abnormalities. Median number of prior therapies was 3 (range: 1–13), with 39% of pts refractory to prior bortezomib, 14% to carfilzomib, 53% to lenalidomide, and 21% to pomalidomide.

Median time on study was 5.9 months (range: 0.3–29.8). Forty-six (70%) pts discontinued, with 36 due to disease progression (PD). Common AEs in ≥30% of pts were diarrhea (46%), constipation (41%), thrombocytopenia (39%), nausea (38%), peripheral neuropathy (33%), and insomnia (32%). Common grade 3/4 AEs in ≥10% of pts were thrombocytopenia (29%), anemia (15%) and neutropenia (14%). Serious AEs in ≥2 pts were febrile neutropenia, thrombocytopenia, cardiac failure, pyrexia, influenza, lower respiratory tract infection, pneumonia, sepsis, acute kidney injury, respiratory failure, embolism, and hypotension. Dose-limiting toxicities were grade 3 cardiac failure in the 300mg cohort (possibly related to dexamethasone) and grade 3 thrombocytopenia during the first cycle in the safety expansion. No events of laboratory or clinical TLS were reported. Four deaths were due to PD and 1 due to respiratory syncytial virus infection.
Overall response rate (ORR) for all pts was 67% (44/66); 28 (42%) pts achieved very good partial response (VGPR) or better (3 stringent complete response [sCR], 10 CR, 15 VGPR). Pts non-refractory to prior proteasome inhibitors (PI) or immunomodulatory drugs (IMiDs) had higher ORR than refractory pts (PI, 92% vs 32%; IMiDs, 82% vs 57%). Among pts refractory to any 2 or more (n=15), 3 or more (n=7), or all 4 (n=4) prior therapies (bortezomib, carfilzomib, lenalidomide, pomalidomide), ORR was 40%, 43%, and 25%, respectively. Median time to progression (~10 vs 3 months) and duration of response (~10 vs 7 months) were longer for pts not refractory to any of these therapies versus refractory pts. ORR for pts with or without cytogenetic abnormalities, respectively, was as follows: 78% vs 65% for t(11;14), 60% vs 67% for t(4;14), 47% vs 73% for del(17p), and 63% vs 69% for del(13q).

Conclusion
VEN combined with bortezomib and dexamethasone has an acceptable safety profile with promising anti-myeloma activity, and the highest response rates were observed in R/R MM pts who were not refractory to PI or IMiDs. These data support the ongoing phase 3 trial with this regimen in R/R MM.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

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