TY - JOUR
T1 - Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma
AU - Costa, Luciano J.
AU - Davies, Faith E.
AU - Monohan, Gregory P.
AU - Kovacsovics, Tibor
AU - Burwick, Nicholas
AU - Jakubowiak, Andrzej
AU - Kaufman, Jonathan L.
AU - Hong, Wan Jen
AU - Dail, Monique
AU - Salem, Ahmed Hamed
AU - Yang, Xiaoqing
AU - Masud, Abdullah A.
AU - Munasinghe, Wijith
AU - Ross, Jeremy A.
AU - Bueno, Orlando F.
AU - Kumar, Shaji K.
AU - Stadtmauer, Edward A.
N1 - Funding Information:
Conflict-of-interest disclosure: L.J.C. has received honoraria from Amgen, Celgene, and Sanofi and research funding from AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Karyopharm Therapeutics. F.E.D. has received honoraria from Adaptive Biotechnologies; has served in a consultancy or advisory role for Amgen, Bristol-Myers Squibb, Celgene, Janssen, Oncopeptides, Roche, Sanofi, and Takeda; has received travel support from Bristol-Myers Squibb, Cel-gene, Janssen, Roche, and Takeda; and has received research funding from Bristol-Myers Squibb, Celgene, and Janssen. G.P.M. has stock or other ownership in EI Dupont, Johnson & Johnson, Novartis, and Pfizer. T.K. has received honoraria from Amgen and Celgene and research funding from AbbVie, Amgen, Janssen, and Prothena. A.J. has served in a consultancy/advisory role with honoraria for AbbVie, Amgen, Bristol-Myers Squibb/Celgene, GSK, Janssen, Juno, and Kar-yopharm. J.L.K. has received honoraria from Tecnofarma; served in a consultancy or advisory role for Amgen, Bristol-Myers Squibb, Cel-gene, Janssen, Karyopharm Therapeutics, Sanofi, Takeda, Tecno-farma, and TG Therapeutics; has received travel support from Amgen, Bristol-Myers Squibb, Celgene, Janssen, Sanofi, and Takeda; and has received research funding from AbbVie/Genentech, Amgen, Bristol-Myers Squibb, Celgene, Fortis Therapeutics, Janssen, Merck, and Sutro Biopharma. W.-J.H. and M.D. report employment with Gen-entech/Roche; have stock or other ownership in Roche; and have received travel support from Genentech/Roche. A.H.S., J.A.R., X.Y., A.A.M., W.M., and O.F.B report employment with AbbVie and may hold stock or other options. S.K.K. has served in a consultancy or advisory role for AbbVie, Adaptive Biotechnologies, Amgen, Bluebird Bio, Celgene, Genecentrix, Genentech/Roche, Janssen Oncology, Kite Pharma, Merck, Molecular Partners, Oncopeptides, and Takeda; and has received research funding from AbbVie, Carsgen Therapeutics Ltd, Celgene, Janssen Oncology, Kite Pharma, MedImmune, Merck, Novartis, Roche/Genentech, Sanofi, Takeda, and TeneoBio. E.A.S. has served in consultancy or advisory roles for Amgen, Cel-gene, Janssen, Novartis, Sanofi, Takeda, and Teva, and has received research funding from AbbVie/Genentech. N.B. declares no competing financial interests.
Funding Information:
Medical writing support was provided by Ashley Skorusa and Grace Lewis of Bio Connections, LLC, funded by AbbVie.
Funding Information:
The authors thank the patients and their families, study coordinators, and support staff. Venetoclax is being developed in a collaboration between AbbVie and Genentech. AbbVie and Genentech sponsored the study and participated in the design, study conduct, collection, analysis, and interpretation of the data, and the writing, review, and approval of the publication. No honoraria or payments were made for authorship. Venetoclax is a BCL-2 inhibitor that is FDA approved for some indications. MM is not an approved indication for treatment with venetoclax. Medical writing support was provided by Ashley Skorusa and Grace Lewis of Bio Connections, LLC, funded by AbbVie.
Publisher Copyright:
ß 2021 by The American Society of Hematology
PY - 2021/10/12
Y1 - 2021/10/12
N2 - Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n 5 13), and 75% in patients without (n 5 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.
AB - Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n 5 13), and 75% in patients without (n 5 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.
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U2 - 10.1182/bloodadvances.2020004146
DO - 10.1182/bloodadvances.2020004146
M3 - Article
C2 - 34470049
AN - SCOPUS:85117042034
VL - 5
SP - 3748
EP - 3759
JO - Blood advances
JF - Blood advances
SN - 2473-9529
IS - 19
ER -