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A Study of Combination Therapy With Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Subjects With Relapsed or Refractory Multiple Myeloma

Trial Status: Active

This is a study of venetoclax, daratumumab, and dexamethasone with and without bortezomib combination therapy to evaluate safety, tolerability, and efficacy of these combinations in participants with relapsed or refractory multiple myeloma. The study will consist of 3 distinct parts: Part 1 includes participants with t(11;14) positive relapsed / refractory (R / R) multiple myeloma who will receive venetoclax in combination with daratumumab and dexamethasone (VenDd); Part 2 includes participants with R / R multiple myeloma who will receive venetoclax in combination with daratumumab, bortezomib, and dexamethasone (VenDVd); Part 3 includes participants with t(11;14) positive R / R multiple myeloma who will receive venetoclax in combination with daratumumab and dexamethasone (VenDd) or daratumumab, bortezomib, and dexamethasone (DVd). Part 1 and Part 2 are non-randomized and will be initiated with a dose-escalation phase in which increasing doses of venetoclax will be given with fixed doses of daratumumab and dexamethasone (Part 1a) or with fixed doses of daratumumab, bortezomib, and dexamethasone (Part 2a). Each dose escalation phase will be followed by a single-arm, open-label expansion phase. Part 3 will include a randomized, open-label expansion phase with participants receiving venetoclax in combination with daratumumab and dexamethasone (VenDd) or daratumumab, bortezomib, and dexamethasone (DVd).

Inclusion Criteria

  • Eastern Cooperative Oncology Group (ECOG) performance status <= 2.
  • Participant has relapsed or refractory multiple myeloma with documented evidence of progression that occurred during or after the participant's last treatment regimen based on investigator's determination of International Myeloma Working Group (IMWG) criteria.
  • Measurable disease confirmed by central lab at Screening, defined by at least 1 of the following: Serum M-protein >= 1.0 g/dL (>= 10 g/L), OR Urine M-protein >= 200 mg/24 hours, OR Serum free light chain (FLC) >= 10 mg/dL, provided serum FLC ratio is abnormal in participants who do not have measurable disease by Serum Protein Electrophoresis (SPEP) or Urine Protein Electrophoresis (UPEP) criteria.
  • Participant has received previous multiple myeloma treatment as defined in the protocol.
  • Bone marrow aspirate samples have been collected.
  • To qualify for Part 1 and 3, the participant must be t(11;14) positive as determined by an analytically validated Fluorescent In Situ Hybridization (FISH) assay per central laboratory testing.
  • Participants must have adequate hematologic, renal and hepatic function.

Exclusion Criteria

  • Previous treatment with venetoclax or other B-Cell Lymphoma 2 (BCL-2) inhibitor OR previous treatment with daratumumab or other anti-CD38 therapy.
  • For participants in Part 2 and 3:
  • Participant is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the last dose of a proteasome inhibitor-containing regimen.
  • Participant has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study drug.
  • Treatment with anti-myeloma chemotherapy, radiotherapy, biological, immunotherapy or an investigational therapy, including targeted small molecule agents within 2 weeks or 5 half-lives (whichever is longer and/or applicable) before first dose.
  • Treatment with anti-myeloma monoclonal antibodies within 6 weeks prior first dose.
  • Recent corticosteroid therapy at a cumulative dose equivalent to >= 140 mg of prednisone or a single dose equivalent to >= 40 mg of dexamethasone within 2 weeks prior the first dose of study drug.
  • Known meningeal involvement of multiple myeloma.
  • Significant history of medical conditions as listed in the protocol.
  • History of other active malignancies including myelodysplastic syndromes (MDS) within the past 3 years with the exceptions of:
  • Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin.
  • Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment
  • Previous malignancy with no evidence of disease confirmed and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.


University of Colorado Hospital


Moffitt Cancer Center
Contact: Rachid C. Baz
Phone: 813-745-8212


Emory University Hospital / Winship Cancer Institute
Status: ACTIVE


University of Chicago Comprehensive Cancer Center
Status: ACTIVE


Brigham and Women's Hospital
Dana-Farber Cancer Institute

New York

Roswell Park Cancer Institute

North Carolina

Duke University Medical Center
Status: ACTIVE


OHSU Knight Cancer Institute
Status: ACTIVE


Fred Hutch / University of Washington Cancer Consortium

Trial Phase Phase II

Trial Type Treatment

Lead Organization

  • Primary ID M15-654
  • Secondary IDs NCI-2018-00251, 2017-002099-26
  • ID NCT03314181