A Phase 1/2, Multicenter, Dose-Escalation and Expansion Study of Combination Therapy with Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Subjects with Relapsed or Refractory Multiple Myeloma
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).
- 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)
- 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
- 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.
- 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
- 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
- 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
- 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
- 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).