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

NCT03314181 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: M15-6542017-002099-26
• Study Type: interventional
• Target: 156
• Locations: 7 countries
• Sites: 40

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

Keywords

t(11,14) positive relapsed/refractory (R/R) multiple myeloma; Non-refractory Relapsed Multiple Myeloma; Non-refractory Refractory Multiple Myeloma; Relapsed Multiple Myeloma; Refractory Multiple Myeloma; Multiple Myeloma; Cancer; Venetoclax; Venclexta

Outcome Measures

Primary Outcomes (8)

• Overall Response Rate (ORR)

  ORR is defined as the percentage of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria.

  Up to approximately 3.5 years after the last participant is enrolled

• Very Good Partial Response or Better Response Rate (VGPR)

  VGPR or better response rate is defined as the proportion of participants with documented VGPR or better (sCR, CR. or VGPR) based on IMWG criteria.

  Up to approximately 3.5 years after the last participant is enrolled

• Complete Response (CR) or Better Rate

  CR or better response is defined as the percentage of participants with documented response of CR or better (stringent complete response \[sCR\] or CR) based on IMWG criteria.

  Up to approximately 3.5 years after the last participant is enrolled

• Time to Response (TTR)

  TTR is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of first documented response of PR or better.

  Up to approximately 3.5 years after the last participant is enrolled

• Duration of Response (DOR)

  DOR is defined as the number of days from the participant's date of first documented response (PR or better) to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first.

  Up to approximately 3.5 years after the last participant is enrolled

• Time to Progression (TTP)

  TTP is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of first documented PD or death due to MM, whichever occurs first.

  Up to approximately 3.5 years after the last participant is enrolled

• Progression-Free Survival (PFS)

  PFS is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of the first documented PD or death due to any cause, whichever occurs first.

  Up to approximately 3.5 years after the last participant is enrolled

• Overall Survival (OS)

  OS is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of death.

  Up to approximately 3.5 years after the last participant is enrolled

Secondary Outcomes (4)

• Minimal Residual Disease (MRD)

  Up to 12 months after confirmation of Complete Response (CR) or Stringent Complete Response (sCR)

• Cmax of Venetoclax

  Up to approximately 1 year

• Tmax of Venetoclax

  Up to approximately 1 year

• AUC0-24 of Venetoclax

  Up to approximately 1 year

Study Arms (7)

Arm A, Part 1a: VenDd Dose Escalation

EXPERIMENTAL

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).

Drug: Dexamethasone; Drug: Daratumumab; Drug: Venetoclax

Arm B, Part 1b: VenDd Dose Expansion

EXPERIMENTAL

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).

Drug: Dexamethasone; Drug: Daratumumab; Drug: Venetoclax

Arm D, Part 2a: VenDVd Dose Escalation

EXPERIMENTAL

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+.

Drug: Dexamethasone; Drug: Daratumumab; Drug: Venetoclax; Drug: Bortezomib

Arm E, Part 2b: VenDVd Dose Expansion

EXPERIMENTAL

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+.

Drug: Dexamethasone; Drug: Daratumumab; Drug: Venetoclax; Drug: Bortezomib

Arm F: VenDd Dose Expansion

EXPERIMENTAL

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).

Drug: Dexamethasone; Drug: Daratumumab; Drug: Venetoclax

Arm G: VenDd Dose Expansion

EXPERIMENTAL

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).

Drug: Dexamethasone; Drug: Daratumumab; Drug: Venetoclax

Arm H: DVd Dose

ACTIVE COMPARATOR

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

Drug: Dexamethasone; Drug: Daratumumab; Drug: Bortezomib

Interventions

Dexamethasone DRUG

Infusion; Intravenous (IV), or Tablet; Oral

Arm A, Part 1a: VenDd Dose Escalation; Arm B, Part 1b: VenDd Dose Expansion; Arm D, Part 2a: VenDVd Dose Escalation; Arm E, Part 2b: VenDVd Dose Expansion; Arm F: VenDd Dose Expansion; Arm G: VenDd Dose Expansion; Arm H: DVd Dose

Daratumumab DRUG

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

Arm A, Part 1a: VenDd Dose Escalation; Arm B, Part 1b: VenDd Dose Expansion; Arm D, Part 2a: VenDVd Dose Escalation; Arm E, Part 2b: VenDVd Dose Expansion; Arm F: VenDd Dose Expansion; Arm G: VenDd Dose Expansion; Arm H: DVd Dose

Venetoclax DRUG

Tablet; Oral

Also known as: ABT-199, Venclexta

Arm A, Part 1a: VenDd Dose Escalation; Arm B, Part 1b: VenDd Dose Expansion; Arm D, Part 2a: VenDVd Dose Escalation; Arm E, Part 2b: VenDVd Dose Expansion; Arm F: VenDd Dose Expansion; Arm G: VenDd Dose Expansion

Bortezomib DRUG

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

Arm D, Part 2a: VenDVd Dose Escalation; Arm E, Part 2b: VenDVd Dose Expansion; Arm H: DVd Dose

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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:

Sponsors & Collaborators

• AbbVie: lead
• Janssen Research & Development, LLC: collaborator

Study Sites (40)

Univ of Colorado Cancer Center /ID# 167331

Aurora, Colorado, 80045, United States

Location

Moffitt Cancer Center /ID# 169614

Tampa, Florida, 33612-9416, United States

Location

Winship Cancer Institute of Emory University /ID# 165427

Atlanta, Georgia, 30322, United States

Location

The University of Chicago Medical Center /ID# 165429

Chicago, Illinois, 60637-1443, United States

Location

Beth Israel Deaconess Medical Center /ID# 210904

Boston, Massachusetts, 02215-5400, United States

Location

Dana-Farber Cancer Institute /ID# 166886

Boston, Massachusetts, 02215, United States

Location

Hackensack Univ Med Ctr /ID# 225111

Hackensack, New Jersey, 07601, United States

Location

Duplicate_Roswell Park Comprehensive Cancer Center /ID# 169615

Buffalo, New York, 14263, United States

Location

Weill Cornell Medicine/NYP /ID# 167605

New York, New York, 10021-4872, United States

Location

Atrium Health Carolinas Medical Center /ID# 164948

Charlotte, North Carolina, 28203, United States

Location

Duke Cancer Center /ID# 165104

Durham, North Carolina, 27710-3000, United States

Location

Duplicate_Wake Forest Baptist Health /ID# 224447

Winston-Salem, North Carolina, 27157-0001, United States

Location

Oregon Health and Science University /ID# 166822

Portland, Oregon, 97239, United States

Location

University of Washington /ID# 164884

Seattle, Washington, 98109, United States

Location

The Kinghorn Cancer Centre /ID# 165431

Darlinghurst, New South Wales, 2010, Australia

Location

St George Hospital /ID# 171063

Kogarah, New South Wales, 2217, Australia

Location

Duplicate_Royal Adelaide Hospital /ID# 171060

Adelaide, South Australia, 5000, Australia

Location

Eastern Health /ID# 165850

Box Hill, Victoria, 3128, Australia

Location

St Vincent's Hospital Melbourne /ID# 165853

Fitzroy Melbourne, Victoria, 3065, Australia

Location

Peter MacCallum Cancer Ctr /ID# 164742

Melbourne, Victoria, 3000, Australia

Location

Duplicate_Royal Perth Hospital /ID# 224895

Perth, Western Australia, 6000, Australia

Location

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

Calgary, Alberta, T2N 5G2, Canada

Location

Cross Cancer Institute /ID# 203114

Edmonton, Alberta, T6G 1Z2, Canada

Location

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

Montreal, Quebec, H4A 3J1, Canada

Location

Rigshospitalet /ID# 164420

Copenhagen Ø, Capital Region, 2100, Denmark

Location

Duplicate_Aarhus University Hospital /ID# 164509

Aarhus N, Central Jutland, 8200, Denmark

Location

Odense University Hospital /ID# 164417

Odense, Region Syddanmark, 5000, Denmark

Location

Sygehus Lillebalt, Vejle /ID# 164418

Vejle, Region Syddanmark, 7100, Denmark

Location

CHU Limoges - Dupuytren 1 /ID# 224759

Limoges, Franche-Comte, 87042, France

Location

CHRU Tours - Hopital Bretonneau /ID# 164795

Tours, Indre-et-Loire, 37044, France

Location

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

Nantes, Pays de la Loire Region, 44000, France

Location

Institut Gustave Roussy /ID# 164807

Villejuif, Val-de-Marne, 94805, France

Location

CHU Poitiers - La miletrie /ID# 164806

Poitiers, Vienne, 86000, France

Location

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

Paris, 75010, France

Location

Universitaetsklinikum Freiburg /ID# 166036

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

University Hospital Cologne /ID# 166037

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Nagoya City University Hospital /ID# 225273

Nagoya, Aichi-ken, 467-8602, Japan

Location

Kameda General Hospital /ID# 225246

Kamogawa-shi, Chiba, 296-8602, Japan

Location

Duplicate_Matsuyama Red Cross Hospital /ID# 225196

Matsuyama, Ehime, 790-8524, Japan

Location

Gifu Municipal Hospital /ID# 240381

Gifu, Gifu, 500-8323, Japan

Location

Related Publications (1)

• 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.

  PMID: 34388020 DERIVED

Related Links

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

MeSH Terms

Conditions

Multiple Myeloma; Neoplasms

Interventions

Dexamethasone; daratumumab; venetoclax; Bortezomib

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• ABBVIE INC.

  AbbVie

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: October 11, 2017
• First Posted: October 19, 2017
• Study Start: April 2, 2018
• Primary Completion (Estimated): May 1, 2031
• Study Completion (Estimated): May 1, 2031
• Last Updated: August 14, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• Time Frame: For details on when studies are available for sharing visit https://vivli.org/ourmember/abbvie/
• Access Criteria: To learn more about the process, or to submit a request, visit the following link https://www.abbvieclinicaltrials.com/hcp/data-sharing/

Locations

FR (6); DE (2); JP (4); CA (3); AU (7); US (14); DK (4)