Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14)

Abstract

Purpose: Venetoclax is an oral BCL-2 inhibitor with single-agent activity in patients with relapsed or refractory multiple myeloma (RRMM) with t(11;14) translocation. Venetoclax efficacy in RRMM may be potentiated through combination with agents including bortezomib, dexamethasone, and daratumumab.

Methods: This phase I study (NCT03314181) evaluated venetoclax with daratumumab and dexamethasone (VenDd) in patients with t(11;14) RRMM and VenDd with bortezomib (VenDVd) in cytogenetically unselected patients with RRMM. Primary objectives included expansion-phase dosing, safety, and overall response rate. Secondary objectives included further safety analysis, progression-free survival, duration of response, time to progression, and minimal residual disease negativity.

Results: Forty-eight patients were enrolled, 24 each in parts 1 (VenDd) and 2 (VenDVd). There was one dose-limiting toxicity in part 1 (grade 3 febrile neutropenia, 800 mg VenDd). Common adverse events with VenDd and VenDVd included diarrhea (63% and 54%) and nausea (50% and 50%); grade ≥ 3 adverse events were observed in 88% in the VenDd group and 71% in the VenDVd group. One treatment-emergent death occurred in part 2 (sepsis) in the context of progressive disease, with no other infection-related deaths on study with medians of 20.9 and 20.4 months of follow-up in parts 1 and 2, respectively. The overall response rate was 96% with VenDd (all very good partial response or better [≥ VGPR]) and 92% with VenDVd (79% ≥ VGPR). The 18-month progression-free survival rate was 90.5% (95% CI, 67.0 to 97.5) with VenDd and 66.7% (95% CI, 42.5 to 82.5) with VenDVd.

Conclusion: VenDd and VenDVd produced a high rate of deep and durable responses in patients with RRMM. These results support continued evaluation of venetoclax with daratumumab regimens to treat RRMM, particularly in those with t(11;14).

Conflict of interest statement

Nizar J. BahlisHonoraria: Celgene, Janssen, AbbVie, Amgen, Sanofi, Takeda, Karyopharm Therapeutics, GlaxoSmithKline, Genentech/RocheConsulting or Advisory Role: Janssen, Celgene, Amgen, Sanofi, Takeda, Pfizer, Karyopharm TherapeuticsResearch Funding: Janssen, Celgene Rachid BazConsulting or Advisory Role: Karyopharm Therapeutics, BMS, AbbVie, Oncopeptides, Shattuck Labs, SanofiResearch Funding: Karyopharm Therapeutics, Celgene, Merck Sharp & Dohme, Takeda, Signal Genetics, AbbVie, Sanofi, Janssen, BMS Simon J. HarrisonHonoraria: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, Haemalogix, SanofiConsulting or Advisory Role: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, Haemalogix, SanofiSpeakers' Bureau: AbbVie, Amgen, Celgene/Bristol Myers Squibb, GlaxoSmithKline, Janssen Cilag, Novartis, Roche/Genentech, Takeda, TerumoResearch Funding: Haemalogix, Janssen CilagExpert Testimony: EUSA Pharma, Terumo Hang QuachConsulting or Advisory Role: GlaxoSmithKline, Celgene, Karyopharm Therapeutics, Janssen-Cilag, CSL Behring, Amgen, SanofiResearch Funding: Celgene, Amgen, Karopharm, GlaxoSmithKline, Sanofi Torben PlesnerConsulting or Advisory Role: Janssen, Celgene, Takeda, AbbVie, Genmab, Oncopeptides, GenentechSpeakers' Bureau: Janssen, TakedaResearch Funding: Janssen, Genmab, Celgene, Takeda, Oncopeptides, Genentech, AbbVie, Roche Philippe MoreauHonoraria: Celgene, Janssen-Cilag, Amgen, GlaxoSmithKline, AbbVie, SanofiConsulting or Advisory Role: Celgene, Janssen, Amgen, GlaxoSmithKline, Sanofi, AbbVie Simon D. GibbsHonoraria: Janssen Oncology, Pfizer, AbbVie, Celgene/Bristol Myers Squibb, AmgenConsulting or Advisory Role: AbbVie Abdullah Al MasudEmployment: AbbVieStock and Other Ownership Interests: AbbVie Jeremy A. RossEmployment: AbbVieStock and Other Ownership Interests: AbbVie Orlando BuenoEmployment: AbbVieStock and Other Ownership Interests: AbbVieResearch Funding: AbbVieTravel, Accommodations, Expenses: AbbVie Jonathan L. KaufmanHonoraria: TecnofarmaConsulting or Advisory Role: Janssen, Celgene, TG Therapeutics, Sanofi, Tecnofarma, GenentechResearch Funding: Merck, Celgene, Janssen, Sutro Biopharma, Fortis, Amgen, AbbVie/Genentech, Bristol Myers SquibbTravel, Accommodations, Expenses: Janssen, Celgene, Bristol Myers Squibb, Sanofi, Amgen, TakedaNo other potential conflicts of interest were reported.

Figures

FIG 1.

(A) Response rates and (B) MRD negativity rates in patients treated with VenDd in part 1a and those treated with VenDVd in part 2.b aThe 95% CIs for response rates in part 1 were 78.9 to 99.9 for ORR, 36.6 to 77.9 for ≥ CR, and 78.9 to 99.9 for ≥ VGPR. bThe 95% CIs for response rates in part 2 were 73.0 to 99.0 for ORR, 25.6 to 67.2 for ≥ CR, and 57.8 to 92.9 for ≥ VGPR. CR, complete response; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response; VenDd, venetoclax, daratumumab, and dexamethasone; VenDVd, venetoclax, daratumumab, bortezomib, and dexamethasone.

FIG 2.

Best change in primary M-protein levels. Ven, Venetoclax; VenDd, venetoclax, daratumumab, and dexamethasone; VenDVd, venetoclax, daratumumab, bortezomib, and dexamethasone.

FIG 3.

Swimlane plot showing best responses, disease progressions, and time on study. CR, complete response; MRD, minimal residual disease; PD, progressive disease; PFS, progression-free survival; PR, partial response; sCR, stringent complete response; SD, stable disease; VenDd, venetoclax, daratumumab, and dexamethasone; VenDVd, venetoclax, daratumumab, bortezomib, and dexamethasone; VGPR, very good partial response.

FIG 4.

PFS in (A) patients treated with VenDd in part 1 and (B) those treated with VenDVd in part 2, and OS in (C) patients treated with VenDd in part 1 and (D) those treated with VenDVd in part 2. Dashed lines represent 95% CI bands. NE, not estimable; NR, not reached; OS, overall survival; PFS, progression-free survival; VenDd, venetoclax, daratumumab, and dexamethasone; VenDVd, venetoclax, daratumumab, bortezomib, and dexamethasone.