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

NCT ID: NCT03314181

Last Updated: 2025-08-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 156 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-04-02
• Study Completion Date: 2031-05-31

Brief Summary

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).

Conditions

Multiple Myeloma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A, Part 1a: VenDd Dose Escalation

Venetoclax (Ven) various doses administered orally, once daily (QD) in combination with daratumumab (D) (1800 mg subcutaneous injection (preferred) or 16 mg/kg intravenous \[IV\]) administered in accordance with prescribing information and dexamethasone (d) (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Infusion; Intravenous (IV), or Tablet; Oral

Daratumumab

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Venetoclax

Intervention Type: DRUG

Tablet; Oral

Arm B, Part 1b: VenDd Dose Expansion

Venetoclax at a dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Infusion; Intravenous (IV), or Tablet; Oral

Daratumumab

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Venetoclax

Intervention Type: DRUG

Tablet; Oral

Arm D, Part 2a: VenDVd Dose Escalation

Venetoclax at various doses administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection \[preferred\] or IV) Cycles 1-8, Days 1, 4, 8 and 11), and dexamethasone (oral or IV) 20 mg Cycles 1 - 3, Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 20 mg Cycles 4-8, Days 1,2,4,5,8,9,11 and 12; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) Cycle 9+.

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Infusion; Intravenous (IV), or Tablet; Oral

Daratumumab

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Venetoclax

Intervention Type: DRUG

Tablet; Oral

Bortezomib

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Arm E, Part 2b: VenDVd Dose Expansion

Venetoclax at dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection) Cycles 1-8, Days 1, 4, 8 and 11, and dexamethasone (oral or IV) 20 mg Cycles 1 - 3, Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 20 mg Cycles 4-8, Days 1,2,4,5,8,9,11 and 12; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) Cycle 9+.

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Infusion; Intravenous (IV), or Tablet; Oral

Daratumumab

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Venetoclax

Intervention Type: DRUG

Tablet; Oral

Bortezomib

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Arm F: VenDd Dose Expansion

Venetoclax at a pre-determined dose, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Infusion; Intravenous (IV), or Tablet; Oral

Daratumumab

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Venetoclax

Intervention Type: DRUG

Tablet; Oral

Arm G: VenDd Dose Expansion

Venetoclax at a pre-determined dose, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).

Group Type: EXPERIMENTAL

Dexamethasone

Intervention Type: DRUG

Infusion; Intravenous (IV), or Tablet; Oral

Daratumumab

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Venetoclax

Intervention Type: DRUG

Tablet; Oral

Arm H: DVd Dose

Daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection) Cycles 1-8: Days 1, 4, 8 and 11, and dexamethasone (oral or IV) 20 mg on Cycles 1 - 3: Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) on Cycles 4-8: Days 1,2,4,5,8,9,11 and 12; 20 mg monthly for Cycles 9+: Day 1

Group Type: ACTIVE_COMPARATOR

Dexamethasone

Intervention Type: DRUG

Infusion; Intravenous (IV), or Tablet; Oral

Daratumumab

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Bortezomib

Intervention Type: DRUG

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Interventions

Dexamethasone

Infusion; Intravenous (IV), or Tablet; Oral

Intervention Type: DRUG

Daratumumab

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Intervention Type: DRUG

Venetoclax

Tablet; Oral

Intervention Type: DRUG

Bortezomib

Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Intervention Type: DRUG

Other Intervention Names

ABT-199; Venclexta

Eligibility Criteria

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
• For participants in Parts 1 and 2: Previous treatment with daratumumab or other anti-CD38 therapy. For participants in Part 3: Prior daratumumab or other anti-CD38 antibody therapy exposure that meets ANY of the following criteria:

• Failure to achieve at least a PR to most recent therapy with daratumumab or other anti-CD38 therapy.
• Daratumumab or other anti-CD38 antibody therapy was discontinued due to toxicity.
• Relapse within 60 days of intensive treatment (at least every other week) of daratumumab or other anti-CD38 antibody therapy.
• Prior treatment with daratumumab or other anti-CD38 antibody within 6 months prior to first dose of study drug.
• 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 to first dose.
• Recent corticosteroid therapy at a cumulative dose equivalent to >= 140 mg of prednisone, cumulative dose equivalent to >= 40 mg of dexamethasone, or a single dose equivalent to >= 40 mg of dexamethasone within 2 weeks prior the first dose of study drug.
• Known central nervous system involvement of multiple myeloma.
• Significant history of medical conditions as listed in the protocol.
• History of other active malignancies including myelodysplatic 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.
• Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
• Has a hypersensitivity or allergy to any of the components of study therapy, excipient or boron.
• Known allergies, hypersensitivities, or intolerance to monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products (see daratumumab prescribing information).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Janssen Research & Development, LLC

INDUSTRY

Sponsor Role: collaborator

AbbVie

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

ABBVIE INC.

Role: STUDY_DIRECTOR

AbbVie

Locations

Univ of Colorado Cancer Center /ID# 167331

Aurora, Colorado, United States

Moffitt Cancer Center /ID# 169614

Tampa, Florida, United States

Winship Cancer Institute of Emory University /ID# 165427

Atlanta, Georgia, United States

The University of Chicago Medical Center /ID# 165429

Chicago, Illinois, United States

Beth Israel Deaconess Medical Center /ID# 210904

Boston, Massachusetts, United States

Dana-Farber Cancer Institute /ID# 166886

Boston, Massachusetts, United States

Hackensack Univ Med Ctr /ID# 225111

Hackensack, New Jersey, United States

Duplicate_Roswell Park Comprehensive Cancer Center /ID# 169615

Buffalo, New York, United States

Weill Cornell Medicine/NYP /ID# 167605

New York, New York, United States

Atrium Health Carolinas Medical Center /ID# 164948

Charlotte, North Carolina, United States

Duke Cancer Center /ID# 165104

Durham, North Carolina, United States

Duplicate_Wake Forest Baptist Health /ID# 224447

Winston-Salem, North Carolina, United States

Oregon Health and Science University /ID# 166822

Portland, Oregon, United States

University of Washington /ID# 164884

Seattle, Washington, United States

The Kinghorn Cancer Centre /ID# 165431

Darlinghurst, New South Wales, Australia

St George Hospital /ID# 171063

Kogarah, New South Wales, Australia

Duplicate_Royal Adelaide Hospital /ID# 171060

Adelaide, South Australia, Australia

Eastern Health /ID# 165850

Box Hill, Victoria, Australia

St Vincent's Hospital Melbourne /ID# 165853

Fitzroy Melbourne, Victoria, Australia

Peter MacCallum Cancer Ctr /ID# 164742

Melbourne, Victoria, Australia

Duplicate_Royal Perth Hospital /ID# 224895

Perth, Western Australia, Australia

Arthur J. E. Child Comprehensive Cancer Centre /ID# 167822

Calgary, Alberta, Canada

Cross Cancer Institute /ID# 203114

Edmonton, Alberta, Canada

Disc_Royal Victoria Hospital / McGill University Health Centre /ID# 167824

Montreal, Quebec, Canada

Rigshospitalet /ID# 164420

Copenhagen Ø, Capital Region, Denmark

Duplicate_Aarhus University Hospital /ID# 164509

Aarhus N, Central Jutland, Denmark

Odense University Hospital /ID# 164417

Odense, Region Syddanmark, Denmark

Sygehus Lillebalt, Vejle /ID# 164418

Vejle, Region Syddanmark, Denmark

CHU Limoges - Dupuytren 1 /ID# 224759

Limoges, Franche-Comte, France

CHRU Tours - Hopital Bretonneau /ID# 164795

Tours, Indre-et-Loire, France

Centre Hospitalier Universitaire de Nantes, Hotel Dieu -HME /ID# 164767

Nantes, Pays de la Loire Region, France

Institut Gustave Roussy /ID# 164807

Villejuif, Val-de-Marne, France

CHU Poitiers - La miletrie /ID# 164806

Poitiers, Vienne, France

Duplicate_AP-HP - Hopital Saint-Louis /ID# 224758

Paris, , France

Universitaetsklinikum Freiburg /ID# 166036

Freiburg im Breisgau, Baden-Wurttemberg, Germany

University Hospital Cologne /ID# 166037

Cologne, North Rhine-Westphalia, Germany

Nagoya City University Hospital /ID# 225273

Nagoya, Aichi-ken, Japan

Kameda General Hospital /ID# 225246

Kamogawa-shi, Chiba, Japan

Duplicate_Matsuyama Red Cross Hospital /ID# 225196

Matsuyama, Ehime, Japan

Gifu Municipal Hospital /ID# 240381

Gifu, Gifu, Japan

Countries

United States; Australia; Canada; Denmark; France; Germany; Japan

References

Bahlis NJ, Baz R, Harrison SJ, Quach H, Ho SJ, Vangsted AJ, Plesner T, Moreau P, Gibbs SD, Coppola S, Yang X, Al Masud A, Ross JA, Bueno O, Kaufman JL. 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). J Clin Oncol. 2021 Nov 10;39(32):3602-3612. doi: 10.1200/JCO.21.00443. Epub 2021 Aug 13.

Reference Type: DERIVED

PMID: 34388020 (View on PubMed)

Related Links

http://www.rxabbvie.com

This clinical study may be evaluating a usage that is not currently FDA approved. Please see US Prescribing Information for approved uses.

Other Identifiers

2017-002099-26

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

M15-654

Identifier Type: -

Identifier Source: org_study_id