PMID- 33368455
OWN - NLM
STAT- MEDLINE
DCOM- 20210423
LR  - 20230328
IS  - 1096-8652 (Electronic)
IS  - 0361-8609 (Print)
IS  - 0361-8609 (Linking)
VI  - 96
IP  - 4
DP  - 2021 Apr 1
TI  - Targeting BCL-2 with venetoclax and dexamethasone in patients with 
      relapsed/refractory t(11;14) multiple myeloma.
PG  - 418-427
LID - 10.1002/ajh.26083 [doi]
AB  - Venetoclax (Ven) is a selective small-molecule inhibitor of BCL-2 that exhibits 
      antitumoral activity against MM cells with t(11;14) translocation. We evaluated 
      the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients 
      with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This 
      open-label, multicenter study had two distinct phases (phase one [P1], phase two 
      [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 
      40 mg [20 mg for patients >/=75 years] on days 1, 8, and 15, per 21-day cycle). The 
      primary objective of the P1 VenDex cohort was to assess safety and 
      pharmacokinetics. Phase two further evaluated efficacy with objective response 
      rate (ORR) and very good partial response or better. Correlative studies explored 
      baseline BCL2 (BCL-2) and BCL2L1 (BCL-X(L) ) gene expression, cytogenetics, and 
      recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with 
      t(11;14) positive translocation received VenDex. P1/P2 patients had received a 
      median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. 
      Predominant grade 3/4 hematological adverse events (AEs) with >/=10% occurrence 
      included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), 
      and anemia (5%/16%). At a median follow-up of 12.3/9.2 months, ORR was 60%/48%. 
      The duration of response estimate at 12 months was 50%/61%, and the median time 
      to progression was 12.4/10.8 months. In biomarker evaluable patients, response to 
      VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key 
      oncogenic signaling pathways, including MAPK and NF-kB. VenDex demonstrated 
      efficacy and manageable safety in heavily-pre-treated patients with t(11;14) R/R 
      MM.
CI  - (c) 2020 The Authors. American Journal of Hematology published by Wiley Periodicals 
      LLC.
FAU - Kaufman, Jonathan L
AU  - Kaufman JL
AUID- ORCID: 0000-0002-5687-6429
AD  - Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
FAU - Gasparetto, Cristina
AU  - Gasparetto C
AD  - Duke University, Hematologic Malignancies & Cellular Therapy, Durham, North 
      Carolina, USA.
FAU - Schjesvold, Fredrik H
AU  - Schjesvold FH
AUID- ORCID: 0000-0003-1096-0569
AD  - Oslo Myeloma Center, Oslo University Hospital, Oslo, Norway and K.G. Jebsen 
      Center for B-cell malignancies, University of Oslo, Oslo, Norway.
FAU - Moreau, Philippe
AU  - Moreau P
AUID- ORCID: 0000-0003-1780-8746
AD  - University Hospital, Nantes, France CRCINA, INSERM, Centre National de la 
      Recherche Scientifique, University of Angers, University of Nantes, Nantes, 
      France.
FAU - Touzeau, Cyrille
AU  - Touzeau C
AD  - University Hospital, Nantes, France CRCINA, INSERM, Centre National de la 
      Recherche Scientifique, University of Angers, University of Nantes, Nantes, 
      France.
FAU - Facon, Thierry
AU  - Facon T
AD  - Centre Hospitalier Regional Universitaire Lille, Hospital Huriez, Lille, France.
FAU - Boise, Lawrence H
AU  - Boise LH
AD  - Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
FAU - Jiang, Yanwen
AU  - Jiang Y
AD  - Genentech Inc., South San Francisco, California, USA.
FAU - Yang, Xiaoqing
AU  - Yang X
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Dunbar, Fengjiao
AU  - Dunbar F
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Vishwamitra, Deeksha
AU  - Vishwamitra D
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Unger, Stefanie
AU  - Unger S
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Macartney, Tammy
AU  - Macartney T
AD  - AbbVie Deutschland GmbH & Co KG, Wiesbaden, Germany.
FAU - Pesko, John
AU  - Pesko J
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Yu, Yao
AU  - Yu Y
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Salem, Ahmed Hamed
AU  - Salem AH
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Ross, Jeremy A
AU  - Ross JA
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Hong, Wan-Jen
AU  - Hong WJ
AD  - Genentech Inc., South San Francisco, California, USA.
FAU - Maciag, Paulo C
AU  - Maciag PC
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Pauff, James M
AU  - Pauff JM
AD  - AbbVie Inc, North Chicago, Illinois, USA.
FAU - Kumar, Shaji
AU  - Kumar S
AD  - Mayo Clinic, Rochester, Minnesota, USA.
LA  - eng
GR  - P30 CA014236/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20210119
PL  - United States
TA  - Am J Hematol
JT  - American journal of hematology
JID - 7610369
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (BCL2L1 protein, human)
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Sulfonamides)
RN  - 0 (bcl-X Protein)
RN  - 4Z63YK6E0E (daratumumab)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - N54AIC43PW (venetoclax)
SB  - IM
MH  - Aged
MH  - Antibodies, Monoclonal/pharmacology
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse 
      effects/pharmacokinetics/*therapeutic use
MH  - Bone Marrow/pathology
MH  - Bridged Bicyclo Compounds, Heterocyclic/administration & dosage/adverse 
      effects/pharmacokinetics/*pharmacology
MH  - Chromosomes, Human, Pair 11/genetics
MH  - Chromosomes, Human, Pair 14/genetics
MH  - Combined Modality Therapy
MH  - Dexamethasone/administration & dosage
MH  - Female
MH  - Follow-Up Studies
MH  - Genes, bcl-2
MH  - Hematologic Diseases/chemically induced
MH  - Hematopoietic Stem Cell Transplantation
MH  - Humans
MH  - Infections/etiology
MH  - Kaplan-Meier Estimate
MH  - Male
MH  - Middle Aged
MH  - Multiple Myeloma/*drug therapy/genetics/therapy
MH  - Neoplasm Proteins/*antagonists & inhibitors
MH  - Proto-Oncogene Proteins c-bcl-2/*antagonists & inhibitors
MH  - Recurrence
MH  - *Salvage Therapy
MH  - Signal Transduction
MH  - Sulfonamides/administration & dosage/adverse 
      effects/pharmacokinetics/*pharmacology
MH  - Translocation, Genetic
MH  - bcl-X Protein
PMC - PMC7986778
COIS- JL Kaufman: Consultant for BMS, Janssen and Data Safety Monitoring Board for TG 
      Therapeutics. C Gasparetto: Honoraria from Janssen, BMS, Celgene; Consultant for 
      Janssen, BMS, Celgene; Research support from Celgene; Travel, accommodations, or 
      other expenses paid or reimbursed by Janssen, BMS, Celgene. FH Schjesvold: 
      Adboards for Amgen, Celgene, Takeda, Janssen, Oncopeptides, MSD. Honoraria from 
      Amgen, Celgene, Takeda, Janssen, Novartis, SkyliteDX. P Moreau: Honoraria and 
      advisory boards for AbbVie, Janssen, Celgene/BMS, Amgen. C Touzeau: Advisory 
      board member for AbbVie, Celgene, Janssen, Takeda, Novartis, Amgen. Research 
      funding from AbbVie. T Facon: No relevant conflicts to disclose, investigator in 
      AbbVie funded clinical trial. LH Boise: Advisory board member for Genentech, 
      Research funding and honoraria from AstraZeneca. S Unger, T Macartney, JA Ross, J 
      Pesko, AH Salem, X Yang, F Dunbar, D Vishwamitra, Y Yu: Employees of AbbVie and 
      may own stock. WJ Hong: Employee of Genentech and owns Roche stock and options. Y 
      Jiang: Employee of Genentech and holds Roche stocks. S Kumar: Research support to 
      an institution for clinical trials from Celgene, Millennium/Takeda, Onyx, AbbVie, 
      Janssen, Sanofi, Novartis; Consultant (with no personal compensation) to Celgene, 
      Millennium, BMS, Onyx, Janssen, Noxxon; Honorarium from Skyline. PC Maciag: is a 
      former employee of AbbVie, currently employed by BMS, and may hold AbbVie stock. 
      JM Pauff: is a former employee of AbbVie and currently employed by Sarah Cannon 
      Research Institute. Venetoclax is being developed in collaboration between AbbVie 
      and Genentech. AbbVie and Genentech funded this study (NCT01794520) and 
      participated in the study design, research, analysis, data collection, 
      interpretation of data, reviewing, and approval of the publication. All authors 
      had access to relevant data and participated in the drafting, review, and 
      approval of this manuscript. No honoraria or payments were made for authorship.
EDAT- 2020/12/29 06:00
MHDA- 2021/04/24 06:00
PMCR- 2021/03/23
CRDT- 2020/12/28 12:28
PHST- 2020/12/15 00:00 [received]
PHST- 2020/12/22 00:00 [accepted]
PHST- 2020/12/29 06:00 [pubmed]
PHST- 2021/04/24 06:00 [medline]
PHST- 2020/12/28 12:28 [entrez]
PHST- 2021/03/23 00:00 [pmc-release]
AID - AJH26083 [pii]
AID - 10.1002/ajh.26083 [doi]
PST - ppublish
SO  - Am J Hematol. 2021 Apr 1;96(4):418-427. doi: 10.1002/ajh.26083. Epub 2021 Jan 19.